estradiol-valerate-dienogest and dienogest

The particular features of the pharmacology of a new continuous regimen for hormone replacement therapy containing 2 mg estradiol valerate (E2V) and 2 mg dienogest (DNG) (Climodien, Schering AG, Berlin, Germany) depend largely on its progestogenic component. Dienogest has the essential properties of an effective progestogen, so that it protects against endometrial proliferation and remarkably does not counteract the effects of estrogens. It is a derivative of 19-nortestosterone, but, instead of having an alkyl group at position C17, it has a cyanomethyl group, which endows it with a unique pharmaceutical profile. Its pharmacokinetics make it suitable for oral administration, without accumulation following repeat dosing. The strength of its effect on the endometrium is reflected by the fact that its progestogenic potency (ovulation dose/transformation dose) is about four times greater than that of any other progestogen. It does not bind to sex hormone binding globulin (SHBG), a feature that helps to keep free serum levels of dienogest high and free testosterone levels low. The low antiestrogenicity of dienogest has been well demonstrated in studies of estrogen-related parameters, such as SHBG levels and vasodilatation markers (cyclic guanosine monophosphate, 5-hydroxylindole acetic acid). Receptor binding studies show similar antiandrogenic effects for dienogest and cyproterone acetate, although the Hershberger test of clinical androgenicity suggests that dienogest is not as strongly antiandrogenic as cyproterone acetate, but is more antiandrogenic than chlormadinone acetate or drospirenone. In summary, E2V/DNG is well suited as an effective hormone replacement therapy, with the potential for good bleeding patterns and low androgenicity, owing to its formulation with a progestogenic component that is highly endometriotropic, has low antiestrogenicity and exhibits considerable antiandrogenicity.

Topics: Drug Administration Schedule; Drug Combinations; Endometrium; Estradiol; Female; Humans; Nandrolone

A combination of 2 mg estradiol valerate with 2 mg dienogest (E2V/DNG) (Climodien, Schering AG, Berlin, Gemany) is the first continuous combined postmenopausal hormone replacement therapy (HRT) preparation to contain a progestogen with substantial antiandrogenic activity. A study of its clinical efficacy and safety in a comparative study versus a combination of 2 mg estradiol with 1 mg norethisterone acetate (E2/NETA) has shown both preparations to be highly effective in achieving a rapid response in women with postmenopausal symptoms, in terms of hot flushes and the Kupperman index. Biopsy and ultrasound studies have demonstrated that E2V/DNG quickly and effectively achieved endometrial atrophy in the vast majority of subjects, suggesting a protective role in endometrial proliferation. Data on PP-14 (glycodelin) levels may indicate that E2V/DNG is even more effective than E2/NETA in maintaining endometrial atrophy. No-bleed rates with E2V/DNG at 1, 6 and 12 months were at least as favorable as those with other standard HRT products, with evidence that the no-bleed state is attained more quickly with E2V/DNG. The proportions of women with the no-bleed state in a large-scale study (n = 1501) at 1, 6 and 12 months were 71.8%, 76.6% and 86.4%, respectively. Women with irregular bleeding before treatment responded to E2V/DNG in a manner similar to those without bleeding; this concordance was especially marked after five cycles of treatment. In the comparative study, the mean number of days of bleeding over 12 cycles was significantly lower for E2V/DNG than for E2/NETA. Overall, the profiles of adverse events recorded in clinical use were similar in the two preparations, whilst the safety profile of E2V/DNG in the large-scale study was similar to that of other HRT preparations and gave no cause for clinical concern. The 2 mg E2V/2 mg DNG preparation was associated with a favorable lipid profile, whilst a similar combination (2 mg E2V/3 mg DNG) showed no impact on carbohydrate metabolism or hemostasis, compared to placebo. In summary, 2 mg E2V/2 mg DNG is a novel continuous combined HRT preparation that is effective in treating postmenopausal symptoms rapidly, and has a highly favorable bleeding profile. Studies of the safety of 2 mg E2V/2 mg DNG in clinical use have uncovered no factors likely to be disadvantagous in comparison with other HRT products in widespread use.

Topics: Clinical Trials as Topic; Drug Combinations; Endometrium; Estradiol; Estrogen Replacement Therapy; Female; Hot Flashes; Humans; Nandrolone; Uterine Hemorrhage

The influence of a combined estrogen-progestin regimen (Climodien, Lafamme) on auditory event-related potentials (ERPs) was investigated in a double-blind, placebo-controlled, comparative, randomized 3-arm trial phase (Climodien 2/3=estradiol valerate 2 mg+the progestin dienogest 3 mg, EV=estradiol valerate 2 mg, and placebo), followed by an open-label phase in which all patients received Climodien 2/2 (estradiol valerate 2 mg+dienogest 2 mg). Both the double-blind and the open-label phase lasted 2 months. ERPs were recorded from 19 EEG leads in a two-tone odd-ball paradigm in 49 patients aged between 46 and 67 yr with the diagnosis of insomnia (G 47.0) related to postmenopausal syndrome (N 95.1). Climodien reduced standard N1 and target P300 latencies as compared to placebo, while EV did not affect N1 latency but similarly reduced P300 latency. Climodien increased N1, P2 and P300 amplitudes dose-dependently, predominantly at frontal leads. Estrogen alone had only minor effects on ERP amplitudes. The shortening of standard N1 latency and enhancement of N1 and P2 amplitudes indicates a positive effect of Climodien on perceptual processing, most likely due to vigilance improvements also observed in EEG mapping. Concerning target P300, it seems that estradiol is responsible for the improvement in stimulus evaluation time, as reflected by the shortening of the peak latency, while dienogest seems to account for the improvement in cognitive information processing capacity, whereby 3 mg induced a more pronounced augmentation of P300 amplitudes than 2 mg. Based on the spatial distribution of this increase, it can be speculated that Climodien mainly affects the more frontally distributed P3a subcomponent, which is associated with attention and orientation. Furthermore, the observed changes in ERP-components are consistent with recent studies showing significant positive effects of hormone replacement therapy on cholinergic functions. Thus, Climodien seems to be of interest in preventing cognitive decline and treating cognitive disorders in postmenopausal women. Indeed, there is increasing evidence of beneficial effects of estrogen in dementia. Our present findings suggest that the estrogen effects may be augmented by dienogest.

Topics: Affect; Aged; Double-Blind Method; Drug Combinations; Electrophysiology; Estradiol; Event-Related Potentials, P300; Evoked Potentials, Auditory; Female; Hormone Replacement Therapy; Humans; Middle Aged; Nandrolone; Neuropsychological Tests; Postmenopause; Progesterone Congeners; Reaction Time; Sleep Initiation and Maintenance Disorders

Combined hormonal contraception might worsen migraine in sensitive women, especially during the free-hormone interval, and raise concerns about the vascular risk. The characteristics of a contraceptive pill containing estradiol valerate/dienogest (E2V/DNG) might be of potential benefit in women with menstrually related migraine (MRM) who choose to use oral contraception for birth control.. This was a prospective diary-based pilot study. Thirty-two women (age >35 years) [n=18 who had never used combined oral contraceptives (COCs) and n=14 who had previously used COCs] diagnosed with MRMs according to the International Headache Society criteria were included. During the observational period, women filled in a diary with the clinical characteristics of migraine attacks. After a three-cycle run-in period, each subject received a COC containing E2V/DNG (Qlaira®/Natazia®; Bayer HealthCare, Berlin, Germany) administered using an estrogen step-down and progestogen step-up approach. Follow-up evaluations were scheduled at the last cycle of run-in and at the third and sixth cycles of treatment.. The number of migraine attacks was significantly reduced at the third (p<.001) and sixth cycles (p<.001) in comparison with the run-in period. A similar result was evident for the duration (p<.001 at the third and p<.001 at the sixth cycle) as well as for the severity of head pain (p<.001 at the third and p<.001 at the sixth month). Indeed, a significantly lower number of analgesics were used at the third cycle (p<.001) in comparison with baseline, and a further decrease was evident at the sixth cycle (p<.001) in comparison with the third cycle of E2V/DNG use. Interestingly, duration and severity of head pain were significantly correlated with the number of days of dysmenorrhea at the third cycle (r=.89, p=.000 and r=.67, p=.02; respectively) and at the sixth cycle (r=.76, p=.000 and r=.62, p=.04; respectively) in women without complete remission of menstrual cramps during the study period.. The present diary-based pilot study indicates that the use of a pill containing EV2/DNG for six cycles has a positive effect in women with MRM and suggests an association between dysmenorrhea with COCs use as a potential feature of refractory head pain.

Topics: Adult; Analgesics; Body Mass Index; Contraceptives, Oral, Combined; Drug Combinations; Dysmenorrhea; Estradiol; Female; Humans; Italy; Menstruation; Migraine Disorders; Nandrolone; Pilot Projects; Prospective Studies; Treatment Outcome

Insulin resistance may be induced by both the estrogen and progestin component in hormonal contraception. When estrogen dose is reduced from 50 to 20 mcg, the extent of hyperinsulinemia decreases. Recently, the oral combination contraceptive (COC) containing estradiol valerate (E2V) in combination with dienogest (DNG) was developed in a new estrogen step-down, progesterone step-up dosing strategy (Qlaira, Bayer Healthcare Pharmaceuticals). This study was conducted to evaluate of the effect of a 3-month treatment with E2V/DNG on carbohydrate metabolism in women with polycystic ovarian syndrome (PCOS) and insulin resistance.. Study consisted of subjects attending the gynecological clinic of Siena or Pisa, with PCOS and insulin resistance, and without contraindications for the use of COCs. PCOS females (n=20) aged 18 to 33 years were treated with a contraceptive formulation containing E2V/DNG for 3 months. Before treatment and during the third month of therapy, body mass index (BMI) measurement and an oral glucose tolerance test (OGTT) were performed.. Median values of insulin after treatment were lower than median values before treatment. In particular, the median value of insulin at T0 was reduced by 54.6% (p<.001), and the mean difference between time 0 and 30 min was significantly reduced [42.96 (9.99) mU/mL vs 38.00 (15.10) mU/mL; p<.05]. Homeostasis model assessment of insulin resistance levels were significantly decreased following treatment. OGTT after treatment revealed median fasting glucose levels to be stable (p=.895) at T0. At T30, T60, T120 and T180 min, glucose median values were moderately reduced in comparison to median values before treatment. No significant difference was observed between median BMI values before [26 (4.8) kg/m(2)] and after treatment [26 (3.7) kg/m(2)].. Median insulin levels at T0 and the mean difference between time 0 and 30 of insulin following OGTT were significantly reduced than values before treatment with E2V/DNG for 3 months. Median BMI and glucose levels were not significantly modified. Natural estradiol and nonandrogenic progestogen in the Qlaira formulation could be recommended as an oral contraceptive in women with PCOS who are insulin resistant or who are overweight.

Topics: Adolescent; Adult; Blood Glucose; Body Mass Index; Carbohydrate Metabolism; Contraceptives, Oral, Combined; Drug Combinations; Estradiol; Fasting; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Italy; Nandrolone; Overweight; Polycystic Ovary Syndrome; Young Adult