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Dienogest (DNG) as a therapeutic approach in endometriosis. A review of recent clinical studies
Abstract
Since years gestagenes are established as a therapy option in the treatment of endometriosis. Dienogest, propagated as a "new gestagen" from the 19-nortestosteron family, has some special characteristics. DNG has also interesting antiandrogenic effects and a favourable pharmacokinetic. Soon after its discovery in 1979, Dienogest was considered an effective endocrinological therapeutic option because of its strong effects on the human endometrium. Several DNG-studies with established GnRH-analoges did show a comparable efficacy on the study end-point "pain" but less side effects. DNG was introduced to the European market in 2009 as Visanne© with 2 mg/d. Together with GnRH analoga, the available gestagenes and the combined oral contraceptives, Dienogest is an additional effective substance for the endocrinological treatment of the chronic disease endometriosis. Despite DNG seems to offer an effective long-term therapy option for patients with acceptable quality of life, we should keep in mind that DNG is not the end of our efforts to discover innovative approaches in cause and treatment of endometriosis.
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Endometriosis and adenomyosis uteri are the most common benign disorders affecting girls and women after uterine myomas (fibroids), with a prevalence of roughly 5% to 15%. There have been many advances in diagnostic assessment and in our understanding of the disease over the past decade. Steady improvements in treatment have been accompanied by heightened consciousness of the diagnosis among the affected women and the doctors who care for them.
A selective literature search was carried out in the Cochrane and PubMed databases using the key words "endometriosis," "deep infiltrating endometriosis," "endometriosis AND diagnostics," "endometriosis AND surgical therapy," "endometriosis AND endocrine treatment," and others. The AWMF and ESHRE guidelines were also taken in account.
The main manifestations are primary or secondary dysmenorrhea, bleeding disturbances, infertility, dysuria, pain on defecation (dyschezia), cycle-dependent or (later) cycle-independent pelvic pain, nonspecific cycle-associated gastrointestinal or urogenital symptoms. Cycle-associated problems of urination and/or defecation that are due to endometriosis are most common in young, premenopausal women. Whenever such manifestations are present, endometriosis should be considered in the differential diagnosis, and evidence for it should be sought in the clinical history, physical examination, and ultrasound findings. If endometriosis is histologically confirmed and is of the deeply infiltrating kind, the recommended management today is to refer the patient to an endometriosis center.
Dienogest (DNG), a progestin of 19-nortestosterone derivative, has good oral bioavailability and is highly selective for progesterone receptors. Owing to its antiovulatory, antiproliferative activities in endometrial cells, and its inhibitory effects on the secretion of cytokines, DNG is expected to be an effective treatment for endometriosis. Progesterone receptor-binding affinity is higher for DNG than for progesterone. Several pilot studies demonstrated that after 24 weeks of DNG treatment, there was a significant decrease in terms of dysmenorrhea, premenstrual pain, dyspareunia and diffuse pelvic pain. Most of the cases of genital bleeding occurring in the DNG treatment were spotting or breakthrough bleeding, which decreased with continued treatment and resolved either during treatment or after the end of treatment. The therapeutic effects of DNG 2 mg/day and norethisterone acetate 10 mg/day for endometriotic symptoms during a period of 24 weeks were almost similar. The only disadvantage of DNG seems to be the irregular bleeding. Good efficacy and tolerability of DNG in patients with endometriosis have been demonstrated in an open, randomized European clinical trial as compared with norethisterone acetate. In Japan, a Phase III, randomized, double-blind, multicenter, controlled trial was conducted to compare the efficacy and safety of DNG with intranasal buserelin acetate in patients with endometriosis. The study demonstrated that DNG is as effective as intranasal buserelin acetate in alleviating endometriosis symptoms, and causes less bone mineral density loss, resulting in the use on a commercial basis for endometriosis patients in Japan from 2008. This paper provides summarized data on this new promising drug for endometriosis.
Endometriosis is a gynecological condition that affects approximately 10% of women of reproductive age, including 25-40% of infertile women. Dysmenorrhea, dyspareunia and chronic pelvic pain are the most common symptoms. Currently available medical therapies for endometriosis do not cure the disease, but are directed at symptom relief, typically utilizing the hormone responsiveness of endometriotic tissue to induce lesion atrophy. Unfortunately, pain relapse after treatment suspension is a common event. Treatment with pharmacological therapies for endometriosis should be conceived in terms of years, thus agents that must be withdrawn after a few months due to poor tolerability or severe metabolic side effects do not greatly benefit women with symptomatic endometriosis. The characteristics of progestins render this class an ideal pharmacological choice for administration over extended periods. The present paper will review the rationale for using progestins and their mechanism of action in endometriosis. Thereafter, the results obtained by various progestins in the treatment of endometriosis will be evaluated (danazol, gestrinone, norethisterone acetate, desogestrel, cyproterone acetate, megestrol acetate, medroxyprogesterone acetate, and levonorgestrel). A progestin called dienogest, recently introduced for the treatment of endometriosis, will be given special focus, describing its mechanism of action and clinical results.
Dienogest (17α-cyanomethyl-17β-hydroxy-estra-4,9-dien-3-one, VEB Jenapharm, Jena, GDR), an orally active 19-nortestosterone derivative, was used in the treatment of endometriosis. 57 patients (age 17-45 years) were entered into the study. The diagnosis was confirmed by laparoscopy or laparotomy in 56 cases and in one case clinically. All patients have been treated with 2 mg dienogest per day in a progestin only regimen over a period of 6 months. The day after completing the course of dienogest therapy 51 patients underwent laparoscopy. Endometriotic lesions had completely disappeared in 66.7%; in 80.4% a marked improvement was noted, but no effect was visible in 19.6% of the implants. Eighty-four per cent of the women reported symptomatic improvement. The efficacy of dienogest was correlated negatively with the age of the treated women. The major side effects were spotting and decrease of libido. Blood pressure as well as mean body weight remained unaltered. No patient discontinued dienogest therapy due to side effects.
Dienogest is an orally effective progestin which exerts a strong antiestrogenic and progestogenic effect on the endometrium. The transformation dose as evaluated by the Kaufmann test is 0.45 mg per day, which is approximately double that of levonorgestrel (0.25 mg). Preclinical and clinical data show that dienogest exerts no androgenic effects and, due to the lack of an ethinyl group, has a lesser impact on hepatic metabolism than nortestosterone derivatives. Therefore, it is also suitable for long- term treatment. As an effective progestin, dienogest is suitable for reduction of endometriotic lesions and symptoms which are typical of endometriosis. In three clinical studies of a total of 267 patients with endometriosis treated with dienogest, it was demonstrated that 2-4 mg dienogest for 6 months is as effective as danazol, gonadotropin-releasing hormone analogs or other progestins with respect to improvement of dysmenorrhea and pelvic pain, and reduction or disappearance of endometriotic foci. The advantage of dienogest is its safety profile: it showed good tolerability and fewer adverse effects than most of the other known regimens. Dienogest is a favorable alternative for treatment of endometriosis.
To examine whether long-term administration of dienogest following gonadotropin-releasing hormone agonist (GnRH-a) therapy would prolong the relief of pelvic pain while reducing the amount of irregular uterine bleeding.
This was a prospective, non-randomized clinical trial. Among the patients suffering from chronic pelvic pain associated with recurrent endometriosis, Group G (n=38) received GnRH-a for 4-6 months and then dienogest (1 mg/day) for 12 months. The dose of dienogest was increased to 1.5 or 2 mg/day when a patient had uncontrollable uterine bleeding {n=15 (39%)}. Group D (n=33) received only dienogest (2 mg/day) for 12 months. Pelvic pain was assessed using a visual analog scale (VAS). Uterine bleeding was semi-quantified using a pictorial blood loss assessment chart (PBAC).
In Group G, GnRH-a significantly reduced the VAS score for pelvic pain, and alleviation was maintained during the 12-month therapy with dienogest. There was no significant difference in pain reduction between Group G and Group D. The PBAC score during the first 6 months on dienogest was significantly smaller in Group G than in Group D.
Treatment with a GnRH-a followed by long-term dienogest therapy maintains the relief of endometriosis-associated pelvic pain achieved with GnRH-a therapy for at least 12 months. This regimen reduces the amount of irregular uterine bleeding that often occurs during the early phase of dienogest therapy.
We aimed to establish an endometrial autograft model in rats that would allow for repetitive in vivo analyses of angiogenesis. Dienogest (DNG) is an orally active progestin used for the treatment of endometriosis. We investigated whether DNG would affect angiogenesis of the ectopic endometrium in our model.
Mechanically isolated endometrial fragments were transplanted into dorsal skinfold chambers in rats. We analyzed the effect of DNG on angiogenesis of the ectopic endometrium on Days 0, 2, 4, 7, 10 and 14 after transplantation using intravital fluorescence microscopy.
The DNG-administered group showed significant suppression of angiogenesis of endometrial autografts, as indicated by the reduced size of the microvascular network and decreased microvessel density compared with those of control animals. The newly formed microvessels of the DNG-administered group showed consistently elevated diameters and centerline red blood cell velocity was decreased. Immunohistochemistry revealed a significant reduction in the level of perivascular α-smooth muscle actin within endometrial grafts of the DNG-administered group.
DNG inhibited angiogenesis of the ectopic endometrium, with confirmed structural changes in the microvessels.
Hormonal treatment of endometriosis is often continued for long periods and has the potential to affect many essential metabolic processes. The current study aimed to determine the effects and safety of high-dose dienogest as a medical endometriosis therapy.
The effects and safety of high-dose dienogest, 20-30 mg/day for 24 weeks, were examined in 21 women aged 18-52 years with laparoscopically and histologically proven endometriosis stage I-IV (according to revised American Society of Reproductive Medicine criteria). At baseline and week 24, sera were obtained and stored at -20°C prior to analysis.
The study showed no clinically significant effect of high-dose dienogest on thyroid or adrenal function, electrolyte balance or haematopoiesis. High-dose dienogest therapy also had no appreciable effects on glucose and lipid metabolism, liver enzymes or haemostasis. For instance, although dienogest mediated small increases in the haemostatic variables prothrombin fragment 1 + 2, antithrombin III and protein C, final levels (at week 24) remained within normal reference ranges for these parameters. The exception was the HDL-3 cholesterol concentration at week 24 (0.97 mmol/l), which increased beyond the normal range of 0.28-0.64 mmol/l.
This investigation yielded a unique dataset on the safety of high-dose dienogest in endometriosis stage I-IV. High-dose dienogest (20-30 mg/day) had little influence upon all the parameters measured. It is therefore likely that lower doses of dienogest would have similarly neutral safety effects: an important consideration in the use of dienogest for the treatment of endometriosis.
Endometriosis affects 5-15% of women in the general population and 40% of women seeking infertility evaluation. Its etiology and pathogenesis is controversial. Abnormalities of genes involved in the regulation of apoptosis have been thought to play a role in origin. Hence, we investigated the expression of pro-apoptotic and anti-apoptotic genes in eutopic endometrium from women with endometriosis and healthy controls in relation to disease occurrence and severity.
A prospective study in women undergoing laparoscopic surgery for pelvic pain was conducted. In total, 45 women (30 healthy controls and 15 patients) matched inclusion criteria. The mRNA expression of apoptotic genes (p53, Bcl-x(L,S) and Bax) from eutopic endometrium was detected by RT-PCR.
A significant increase in expression of mRNA p53 (1.42 versus 1.02; p<0.05), and Bcl-x(S) (0.41 versus 0.19; p=0.0006) was found in women with endometriosis compared to healthy controls. Insignificantly increased expression was found for Bax (1.22 versus 1.15). The expression of anti-apoptotic Bcl-x(L) was unchanged (1.08 versus 1.07). The Bcl-x(L)/Bcl-x(S) ratio was twofold higher (5.63 versus 2.63) in controls. By stratifying patients by disease stage we have revealed an increased mRNA expression of apoptotic genes in patients with grades III-IV endometriosis compared to those with grades I-II. However, the difference was significant only for Bcl-x(S) expression (p<0.05).
Results suggest that an increased transcription of pro-apoptotic genes (p53 and Bcl-x(S)) in eutopic endometrium is significantly associated with endometriosis, which indicates dysregulation of apoptotic gene transcription associated with disease.
Endometriosis, defined as the presence of endometrial tissue outside the uterus, is a challenging condition associated with substantial morbidity. Management of endometriosis must be individualized according to the desired treatment outcome, whether it is relief of pain, improvement of fertility, or the prevention of recurrence. For alleviation of endometriosis-associated pain, medical treatment is generally successful, with no medical agent being more efficacious than another in spite of significantly differing side-effect profiles. Surgical therapy has also been demonstrated to reduce pain scores in comparison with expectant management, although conservative surgery has been frequently associated with recurrence. The efficacy of combination therapies still remains to be clarified. For treatment of endometriosis-associated infertility, suppressive medical treatment has been proven to be detrimental to fertility and should be discouraged, while surgery is probably efficacious for all stages. Controlled ovarian hyperstimulation with intrauterine insemination is recommended in early-stage and surgically corrected endometriosis. Combined surgery with GnRH analog treatment has been proposed to be first-line therapy, followed by IVF as second-line therapy in advanced cases. More rigorously designed randomized clinical trials focusing on the endocrinological, immunological, and genetic aspects of endometriosis are necessary to refine conclusions regarding the etiopathogenesis and therapeutic innovations of this perplexing disease.
Twenty patients, mostly with severe endometriosis and infertility, were treated with danazol 600 mg daily for six months. Clinical investigation and laboratory tests were done monthly. During treatment most clinical findings and symptoms of endometriosis disappeared within 2 to 3 months, but rectocervical induration and rectocervical pain decreased more slowly. During the 10 months follow-up after discontinuation of danazol, dysmenorrhoea recurred most commonly of all symptoms, but not to the same degree as before treatment and the patients were mainly satisfied. Gonadotrophin and prolactin levels did not alter significantly during treatment. Serum oestradiol and progesterone values were low during the danazol course. Testosterone values increased because of cross-reaction with danazol metabolites in the testosterone assay. Serum transaminase, creatinine, haemoglobin and blood platelet concentrations increased on average, but the changes were reversible. Three conceptions occurred during the period of study.
The effects of a new progestational compound, dienogest (17 alpha-cyanomethyl-17 beta-hydroxy-estra-4,9-dien-3-one) on lipid metabolism have been studied in 84 otherwise healthy women with laparoscopically proven endometriosis. The women, aged 17 to 45, years were treated with 2 mg dienogest in tablet form daily for 24 weeks. The progestin was highly effective on endometriotic lesions and symptoms, showing an objective endoscopic and a subjective symptomatic improvement in 80% and 83% respectively. Triglycerides, total cholesterol, HDL-cholesterol, LDL-cholesterol and the LDL-cholesterol/HDL-cholesterol ratio were determined before and after 1, 3 and 6 months use of the progestin. There was a maximum decrease of -5.8% in HDL-cholesterol and of -6.5% in triglycerides after 6 months of therapy vis-à-vis the pretreatment values. The maximum increase in LDL-cholesterol of +5.0% was recorded by the end of the first month of dienogest ingestion. The LDL-cholesterol/HDL-cholesterol ratio rose from 1.6 to 1.8 during the course of therapy. There were no significant changes. The data suggest that 2 mg dienogest has little influence on lipid metabolism and provides also in this respect a suitable approach to the hormonal therapy of endometriosis.
Medroxyprogesterone acetate was administered orally at the daily dose of 50 mg for four months to 21 symptomatic women with moderate to severe endometriosis, staged according to the American Fertility Society classification. The efficacy of the therapy was evaluated prospectively by the patients' symptomatology, monthly pelvic examinations, and by restaging the disease at second-look laparoscopy during the last week of treatment. The effects of therapy on the serum gonadotropin and ovarian steroid levels and on the endometrium and the implants of endometriosis were also evaluated. Improvement of symptoms, pelvic nodularity, and tenderness occurred in 80% of the patients. The mean stage score of disease by the American Fertility Society classification decreased from 18.2 +/- 2 before therapy to 5.9 +/- 1 after therapy (P less than .005). Amenorrhea, breakthrough bleeding, and persistent cyclic bleeding occurred in 75, 20, and 10% of the patients, respectively. Ovulation was inhibited in all patients, but serum hormone changes were statistically significant only for LH, which decreased from 9.5 +/- 4 to 5.2 +/- 2 IU/L (P less than .001), and estradiol (E2), which decreased from 80 +/- 30 to 46 +/- 26 pg/mL (P less than .02). Atrophic changes and pseudodecidualized reaction occurred in both the endometrium and the implants of endometriosis. In summary, oral medroxyprogesterone acetate is effective in relieving symptoms and objectively improving endometriosis. Besides inducing a pseudodecidualized reaction and atrophic changes in the endometrium and ectopic implants, medroxyprogesterone acetate also suppresses ovulation and the serum levels of both LH and E2.
Between 1983 and 1986 40 patients were treated for external genital endometriosis with the LHRH agonist buserelin. Ovarian suppression was achieved for a period of six months with a dose of 900 to 1,800 mcg per day. In addition to gynecological findings, liver and kidney function and lipid metabolism were checked prior to treatment and at regular intervals during treatment. No deviations from normal ranges were found. The general side effects observed during treatment were as a rule attributable to the buserelin-induced relative estrogen deficiency. The efficacy of the medication in the treatment of endometriosis was demonstrated by control pelviscopy. Since no undesirable metabolic side effects have so far been observed with buserelin, it may be considered an effective new alternative treatment for endometriosis.
Twenty patients with endometriosis diagnosed by laparoscopy were treated with the antiestrogen, antiprogesterone gestrinone (R-2323) for 6 to 8 months. The drug was administered in a dose of 5 mg twice weekly. According to the American Fertility Society's classification of endometriosis, five patients were classified as having mild (Stage I), eight as having moderate (Stage II), and seven as having severe endometriosis (Stage III). All patients became amenorrheic at the end of the second month of treatment, and symptomless at the end of the third month. Of nine women who had the potential and the desire to conceive, three conceived within 3 months after termination of treatment. Two more became pregnant within 1 year, and another, 14 months after termination of treatment. Five pregnancies progressed to term. One patient aborted. Two of the three women who did not conceive had subfertile husbands. Major side effects recorded were seborrhea and acne, which subsided after discontinuation of therapy. Treatment of endometriosis with gestrinone offers the advantage of effective clearing of lesions with relatively low dosage and frees the patient from the daily administration of drugs required by similar conservative hormonal therapies.