Drospirenone Research Articles

Therapeutic tactics with violations of the menstrual cycle caused by ovulative dysfunction

Purpose: presentation of modern data on the pathogenesis of menstrual cycle disorders (NMCs) associated with ovulatory dysfunction, and the effectiveness of their treatment with medication.Basic provisions. It is shown that NMC is the result of violations of the cyclic production of gonadotropic and sex hormones. Among the hormonal drugs for the treatment of NMCs, combined estrogen-progestational oral contraceptives (COCs), especially those with drospirenone (DRSP), are advantageous. The introduction of calcium levomefolate - biologically active form of folatein the composition of COCs containing 30 μg of ethinylestradiol and DRSP has a potentiating effect associated with their noncontraceptive effects due to antiandrogenic and antimineralocorticoid activity. It was shown that calcium levomefolate, which participates in human body metabolism, as a component of COC, has a protective effect on the cardiovascular system (due to a decrease in the level of homocysteinemia) in the syndrome of polycystic ovaries, contributes to reducing obesity.Conclusion. The combination of 30EE/DRSP promotes the normalization of the menstrual cycle and has non-contraceptive effects associated with antiandrogenic and antimineralcorticoid action, and fortification with calcium levomefolate also has a positive effect on the hormonal profile and lipid metabolism, has a protective effect on cardiovascular diseases in women with the metabolic syndrome in polycystic ovaries, contributes to the normalization of weight.

Effects of different progestins on prostaglandin biosynthesis in human endometrial explants

ObjectiveTo compare the effects of chlormadinone acetate (CMA), dienogest (DNG) and drospirenone (DRSP) on prostaglandin biosynthesis in a human endometrial explants model. Study designHuman endometrial explants obtained by aspiration curettage and human endometrial YHES cells were stimulated with interleukin-1β (IL-1β) and exposed to CMA, DNG, DRSP or dexamethasone (DEX; YHES cells). Cellular messenger RNA (mRNA) levels of cyclooxygenase-2 (COX-2) were analyzed by reverse-transcription quantitative real-time polymerase chain reaction. Concentrations of prostaglandin F2α (PGF2α) in culture supernatants were measured by enzyme-linked immunosorbent assay. ResultsCMA exerted after IL-1β stimulation a stronger down-regulation of COX-2 mRNA compared to DNG and DRSP in human explants (−55% vs. −40% and 46%, respectively). The effect of CMA on COX-2 mRNA was significantly stronger (p=.025) than that of DNG. Moreover, the effect of CMA was independent from cycle phase or presence of endometriosis. In order to evaluate the impact of the investigated progestins on effector molecules, PGF2α release was determined in supernatants. Again, CMA reduced the PGF2α release significantly by an average of −60% (p<.01). In contrast, no significant reduction was found for DNG and DRSP. In YHES cells, only DEX but not the progestins under study exerted a significant down-regulating effect (−79%, p<.01) on COX-2 mRNA after IL-1β stimulation. ConclusionAmong the tested progestins, CMA displayed the most consistent suppression of prostaglandin biosynthesis in human endometrial explants. ImplicationAmong three tested progestins, chlormadinone acetate had the most consistent suppressive effect on prostaglandins in endometrial explants. These findings support clinical observations about the efficacy of chlormadinone acetate in dysmenorrhea treatment.

A comparison of combined oral contraceptives containing chlormadinone acetate versus drospirenone for the treatment of acne and dysmenorrhea: a randomized trial

BackgroundOral contraceptives (OCs), aside from contraceptive efficacy, have been widely known for their non-contraceptive benefits. Different progestogens component of the OCs have been shown to improve the skin, hair, menstrual cycle related disorders and dysmenorrhoeic pain. Thus, we compared the efficacy of OCs containing ethinyl estradiol (EE) and chlormadinone acetate (CMA) versus OCs containing EE and drospirenone (DRSP) for the treatment of acne and dysmenorrhea.MethodsThis study was an investigator-blinded, randomized, parallel group study conducted at the Family Planning Clinic, Department of Obstetrics and Gynaecology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. Women aged between 18 and 45 years were randomly assigned into two treatment groups, either EE/CMA at the dosage of 30 mcg/2 mg once daily (OD) or EE/DRSP at the dosage of 30 mcg/3 mg OD. The subjects were evaluated for the OC’s efficacy for the treatment of acne and dysmenorrhea at baseline visit and after 1, 3, and 6 months of treatment.ResultsA total of 180 women were randomized into the study. Each group had 90 women. Baseline characteristics between both groups were comparable. At Month 6, there was a significantly greater reduction of total acne lesion in the EE/CMA group than EE/DRSP (72.2% vs 64.5%; p = 0.009). As per the investigator’s global assessment of acne treatment, a higher proportion of the subjects from the EE/CMA group was rated “excellent” than those from the EE/DRSP (75.3% vs 49.4%). More subjects from the EE/CMA group had graded their improvement in acne as “excellent” compared to the EE/DRSP group (66.3% vs 48.3%). A higher proportion of the subjects in the EE/CMA group reported a decrease in dysmenorrhoeic pain as “much decrease” and “decrease”. The absence of dysmenorrhea pain was more frequently found in the EE/CMA group and significantly seen as early as Month 1 also in the EE/CMA group compared to EE/DRSP (47.2% vs 27.3%, respectively). The treatments were generally well-tolerated in both groups. There were no significant differences between both groups for adverse events.ConclusionsEE/CMA is more effective for the treatment of acne and dysmenorrhea in women with mild to moderate acne vulgaris and dysmenorrhea than EE/DRSP.Trial registrationThai Clinical Trial Registry ID: TCTR20170518001 (date of registration: May 17, 2017; retrospectively registered).

Effects of combined oral contraception containing drospirenone on premenstrual exacerbation of Meniere’s disease: Preliminary study

ObjectivesMeniere's disease is caused by an augmented endolymph pressure in the inner ear; symptoms are vertigo, fluctuating hearing loss and tinnitus. Exacerbations has been noted during premenstrual phase. The study aims to evaluate the effects of a 20 μm Ethinylestradiol (EE) and 3 mg Drospirenone (DRSP) oral contraceptive (20 μmEE/3mgDRSP) in continuous regimen, associated with rehabilitation therapy on Meniere’s disease. Study designThis non-randomized controlled study was performed from October 2015 to October 2017. Forty-two premenopausal women affected by MD with severe distress in the premenstrual phase were enrolled. Sixteen women constituted the study group (Group A), and twenty women constituted the control group (Group B). Group A underwent EE/DRSP therapy and rehabilitation and Group B underwent rehabilitation therapy alone. Stabilometry and the Dizziness Handicap Inventory questionnaire were used to measure vestibular function and distress related to the disease, respectively, at baseline (T0), 3 months (T1) and 6 months (T2). ResultsAt T0, both groups had large, similar areas of stabilometric ellipses (p = NS) that reduced more in Group A than in Group B, at T1 and T2 (p < 0.001). High scores of the DHI (cut-off ≤54) were observed at T0 in both groups (A 66.8 ± 2.8 vs B 65.5 ± 3.6; p = NS). At T1, a gradual improvement in both groups was observed, manly in Group A (A 45.1 ± 3.6 vs B 62.4 ± 4.1; p < 0.001). At T2, the DHI scores were significantly lower in Group A (39.2 ± 3.8) compared to Group B (68.8 ± 3.6) (p < 0.001). ConclusionsDRSP could be effective in reducing the fluid overload typical of the premenstrual phase, improving symptoms of MD. The results support the efficacy of EE/DRSP usage associated with rehabilitation therapy on premenstrual exacerbation of MD.

THE EFFECT OF LOW-DOSE DROSPIRENONE AND 17β-ESTRADIOL FOR CORRECTION OF THE MANIFESTATIONS OF CLIMACTERIC SYNDROME IN POSTMENOPAUSAL WOMEN

Vasomotor symptoms are the most common symptoms of menopause, requiring treatment with estrogen and/or progestogen. Recent international guidelines recognize the need to use the lowest effective dose of hormone replacement therapy. Drospirenone (DR) in combination with 17β-estradiol (E2) is used as hormone therapy (HT) for relief the symptoms and prevention of postmenopausal osteoporosis.The review presents data of 2 large randomized controlled studies that evaluated the lowest effective dose combination DRSP/ E2, the safety of this dose for endometrium, identified features of its pharmacodynamics and pharmacokinetics, depending on various factors. The minimum effective dose for the relief of hot flushes without causing any significant impact on the endometrium is DRSP of 0,25 mg/E2 of 0,5 mg. According to the results of the pharmacokinetic study a correlation between effectiveness of low dose DRSP/E2 with DRSP and E2 exposure levels was showed, and smoking reduces the effectiveness of hormonal therapy. This drug not only copes with moderate to severe hot flushes, but also reduces the incidence of symptoms of vulvovaginal atrophy, improving quality of life.

Estetrol combined with drospirenone: an oral contraceptive with high acceptability, user satisfaction, well-being and favourable body weight control

Objectives: This study evaluated acceptability, user satisfaction, body weight control and general well-being of estetrol (E4) combined with either drospirenone (DRSP) or levonorgestrel (LNG). Methods: In this open-label, multi-centre, dose-finding, 6-cycle study, 396 healthy women of reproductive age were randomised into five treatment groups in a 24/4-day regimen: 15 mg or 20 mg E4 combined with either 3 mg DRSP or 150 μg LNG, and as reference estradiol valerate (E2V) combined with dienogest (DNG). Data on acceptability, user well-being, satisfaction and body weight were collected. Results: The number of completers was the highest in the 15 mg E4/DRSP group (91.1%), and the lowest for 20 mg E4/LNG (70.1%). The largest proportion of treatment satisfaction was reported for 15 mg E4/DRSP (73.1%), and the lowest for 15 mg E4/LNG (50.6%). The number of women willing to continue with the assigned study treatment was the highest in the 15 mg E4/DRSP group (82.1%) and the lowest for 20 mg E4/LNG (58.3%). Well-being with E4/DRSP combinations was statistically significantly better than with E4/LNG combinations: OR (95% CI) 2.00 (1.13; 3.53) and 1.93 (1.06; 3.56) for 15 and 20 mg E4, respectively, and comparable to E2V/DNG. Proportion of women with a 2 kg or more weight loss after 3 and 6 cycles was the highest in the 15 mg E4/DRSP group (30.7 and 36.7%, respectively). Conclusions: The present study shows that 15 mg estetrol combined with 3 mg DRSP is associated with a high-user acceptability and satisfaction, and with a favourable body weight control.

Sex steroids and metabolic responses in mussels Mytilus galloprovincialis exposed to drospirenone

Drospirenone (DRO) is a synthetic progestin derived from 17α-spironolactone with a pharmacological mechanism of action similar to progesterone. Despite its wide use as pharmaceutical and consequent continuous release into the aquatic environment, DRO effects have been poorly investigated on aquatic biota. In order to unravel the toxicity mechanisms of DRO, mussels Mytilus galloprovincialis were exposed for 7 days to different concentrations of DRO, namely 20ng/L (Low; L), 200ng/L (Medium; M), 2000ng/L (High; H) and 10μg/L (Super High; SH) nominal doses. Following exposure, no significant effect was observed on gonad maturation of treated and untreated mussels. The levels of progesterone (P4) and testosterone (T) were measured in mantle/gonad tissues and no significant alteration detected after exposure. However, the application of a protonic nuclear magnetic resonance (1H NMR)-based metabolomics approach enabled a comprehensive assessment of DRO effects in mussels. Specifically, 1H NMR metabolic fingerprints of digestive glands of DRO treated mussel groups were clearly separated from each other and from controls through a principal component analysis (PCA). Moreover, a number of metabolites involved in different metabolic pathways were found to significantly change in DRO-exposed mussels compared to control, suggesting the occurrence of alterations in energy metabolism, amino acids metabolism, and glycerophospholipid metabolism. Overall, despite no changes in gonad maturation and steroids levels were recorded in mussels after DRO exposure, the metabolomics approach demonstrated its effectiveness and high sensitivity in elucidating DRO-induced metabolic disturbances in marine mussels, and thus its usefulness in the environmental risk assessment of pharmaceuticals.

Hormonal contraception: venous and arterial disease

Objectives: The aim of this review was to evaluate whether the biological and epidemiological evidence is concordant in suggesting that levonorgestrel (LNG)-based hormonal contraceptives (HCs) are safer than newer formulations with regard to their effect on the cardiovascular system. Methods: A narrative review was carried out of the modification of risk factors for venous thromboembolism (VTE) and arterial diseases induced by different HCs. Limits and concordance with epidemiological data were addressed. Results: The data indicate general concordance between modifications of risk factors and epidemiology of VTE, with LNG-based HCs showing lower risk compared with most new formulations. Evidence for drospirenone (DRSP)-containing HCs is conflicting. LNG-based HCs are less favourable than HCs containing non-androgenic progestins, particularly DRSP, on risk factors for arterial events. Epidemiological studies do not consistently show a difference in arterial disease outcomes between different HCs; however, by evaluating women up to the age of 50, they do not take into consideration the time lag necessary for atherosclerosis to develop. Conclusions: As a consequence of the different risk factors involved, and the different time lags between HC use and the manifestation of VTE or arterial diseases, the available epidemiological data do not give a reliable estimate of the cardiovascular risk associated with the use of different HCs. LNG-based HCs are safer than newer HCs as regards VTE risk, but biological data indicate that they are less favourable, particularly than HCs containing DRSP, on risk factors for atherosclerosis. Because of the limits of actual epidemiological evidence regarding arterial disease, modifications of arterial risk factors should be taken into consideration when considering individual long-term safety of HC use.

Efficacy and safety of drospirenone 2 mg/17β-estradiol 1 mg hormone therapy in Korean postmenopausal women.

This regulatory post-marketing surveillance study aimed to evaluate the therapeutic efficacy and safety of drospirenone (DRSP) 2 mg/estradiol (E2) 1 mg tablet in Korean postmenopausal women. A total of 4,149 patients were enrolled and the study was conducted at 207 clinical research centers. The patients' source data was collected between November 2006 and November 2012. More than 85% of patients experienced improvement of menopausal symptoms. The most frequently reported adverse events were vaginal bleeding and breast pain; most of the women suffering from these symptoms fully recovered. The incidence of adverse event was higher in patients of younger age (20 to 39 years), in patients with concomitant diseases, previous hormone replacement therapy in medical history, those treated with DRSP 2 mg/E2 1 mg for shorter duration (3 years or less) and in patients using concomitant medication. In conclusion, the results from this large post-marketing surveillance study confirm the efficacy and safety of DRSP 2 mg/E2 1 mg tablet in Korean postmenopausal women.

Voltammetric Determination of Drospirenone on Mercury Film Electrode

A novel high sensitive method of drospirenone (DR) voltammetric determination was successfully developed for the first time. In order to provide repeatability and low limit of detection, mercury film silver based electrode (Hg(Ag)FE) was applied as the working electrode. The electrochemical behavior of drospirenone reduction on Hg(Ag)FE was investigated using cyclic voltammetry. A linear voltammetric response was obtained for analyte in the concentration range from 2.50·10−9 mol L−1 (9.16·10−7 g L−1) to 1.00·10−8 mol L−1 (3.66·10−6 g L−1), with a detection limit of 1.7·10−9 mol L−1 for preconcentration time of 60 s. Repeatability of method was determined as RSD % for drospirenone concentration of 0.05·10−6 mol L−1 as 1.5% (n = 8). The proposed method was successfully applied and validated by studying the recovery of drospirenone in commercially available combined oral contraceptive pills.

Effect of hormone replacement therapy with the anti-mineralocorticoid progestin Drospirenone compared to tibolone on endothelial function and central haemodynamics in post-menopausal women

Drospirenone (DRSP) is an antialdosterone agent with progestogenic and antiandrogenic effects. This compound, has been recently used in combination with 17β-estradiol (E2) as hormonal therapy in postmenopausal women and has been shown to exert a significant antihypertensive effect in hypertensive post-menopausal women. Aim of the present study was to compare the effect of DRSP/E2 with those of Tibolone (T) on endothelial function, arterial stiffness, and lipid profile of early postmenopausal women naïve on post-menopausal hormonal therapy. Twenty-four women met the inclusion criteria and entered the study. Women were randomized to receive either DRSP/E2 or T for 6months. Blood pressure and heart rate were similar in both groups at baseline and at the end of the study. Compared to baseline, endothelial function assessed by Reactive Hyperemia (RH) significantly improved in women receiving E2/DRSP, whereas no significant differences between baseline and follow up were detected in women receiving Tibolone. Women receiving E2/DRSP showed a significant decrease in pulse wave velocity and Augmentation Index compared to baseline while no changes were observed in women receiving Tibolone. The capacity of sera to trigger endothelial cells apoptosis in vitro measured by cell death assay was significantly reduced by E/DRSP but not by T (HFA-E 70±5,6% vs HFD-E 41±4,5%, p<0,001). In conclusion, the present study shows that the association of Estradiol and Drospirenone as hormonal replacement therapy significantly improves vascular parameters and the composition of sera relevant for vascular protection in early post-menopausal normotensive women. These effects are not shared by Tibolone.

Fourth-Generation Progestins Inhibit 3β-Hydroxysteroid Dehydrogenase Type 2 and Modulate the Biosynthesis of Endogenous Steroids.

Progestins used in contraception and hormone replacement therapy are synthetic compounds designed to mimic the actions of the natural hormone progesterone and are classed into four consecutive generations. The biological actions of progestins are primarily determined by their interactions with steroid receptors, and factors such as metabolism, pharmacokinetics, bioavailability and the regulation of endogenous steroid hormone biosynthesis are often overlooked. Although some studies have investigated the effects of select progestins on a few steroidogenic enzymes, studies comparing the effects of progestins from different generations are lacking. This study therefore explored the putative modulatory effects of progestins on de novo steroid synthesis in the adrenal by comparing the effects of select progestins from the respective generations, on endogenous steroid hormone production by the H295R human adrenocortical carcinoma cell line. Ultra-performance liquid chromatography/tandem mass spectrometry analysis showed that the fourth-generation progestins, nestorone (NES), nomegestrol acetate (NoMAC) and drospirenone (DRSP), unlike the progestins selected from the first three generations, modulate the biosynthesis of several endogenous steroids. Subsequent assays performed in COS-1 cells expressing human 3βHSD2, suggest that these progestins modulate the biosynthesis of steroid hormones by inhibiting the activity of 3βHSD2. The Ki values determined for the inhibition of human 3βHSD2 by NES (9.5 ± 0.96 nM), NoMAC (29 ± 7.1 nM) and DRSP (232 ± 38 nM) were within the reported concentration ranges for the contraceptive use of these progestins in vivo. Taken together, our results suggest that newer, fourth-generation progestins may exert both positive and negative physiological effects via the modulation of endogenous steroid hormone biosynthesis.

Commentary on ‘Prescribing patterns of combined hormonal products containing cyproterone acetate, levonorgestrel and drospirenone in the UK’

The research undertaken by Cea-Soriano et al 1 provides for the first time analysis of the prescribing patterns of three combined hormonal contraception (CHC) products with regard to contraceptive and...

Reduced hemostatic effects with drospirenone-based oral contraceptives containing estetrol vs. ethinyl estradiol

The effects of estetrol (E4), a natural fetal estrogen, combined with drospirenone (DRSP) were evaluated on plasma levels of sex hormone-binding globulin (SHBG), angiotensinogen and 12 hemostasis markers. Combinations of 3 mg DRSP with 5 or 10 mg E4 were compared with YAZ® (20 mcg ethinyl estradiol and 3 mg DRSP; EE/DRSP) in parallel groups of 15-18 healthy young women. Main outcome was the relative change from pretreatment to the end (day 24±1) of the third treatment cycle. All E4 combinations showed low estrogen impact compared to EE/DRSP. Effects on SHBG and angiotensinogen of 10 mg E4 combined with DRSP were 15%-20% that of EE/DRSP. Both E4/DRSP combinations reduced D-dimer level and the 5 mg E4/DRSP combination also decreased fragment 1+2. The reduction in coagulation markers suggests an anticoagulant effect from DRSP. The indications of a low thrombosis risk for E4 preparations should be validated in larger studies. IMPLICATION STATEMENT.

The effect of a drospirenone-containing combined oral contraceptive on female sexual function: a prospective randomised study

Objectives: The study investigated the effects on female sexual function of a progestogen-containing combined oral contraceptives (COCs) with an antiandrogenic profile taken in a continuous regimen.Methods: In this prospective randomised single-institution study, 80 healthy women with a monogamous partner and an active sexual life were randomised into two groups for a period of 3 months. Women in the exposed group (n = 40) took a COCs containing 30 μg ethinylestradiol (EE) and 3 mg drospirenone (DRSP) in a 21/7 regimen. Women in the control group (n = 40) used either a barrier contraceptive method (BCM) or a natural family planning method (NFPM). Participants were asked to complete a set of validated questionnaires to assess sociodemographic variables and measure Female Sexual Function Index (FSFI).Results: The total FSFI score (p < 0.0001), as well as the desire (p = 0.04) and arousal (p = 0.03) scores, were significantly lower in the COCs group after 3 months of hormonal contraceptive use compared with baseline. Women using BCM or NFPM showed an improvement in total FSFI score (p = 0.02). Hormonal contraception with DRSP increased the likelihood of worse sexual function in the desire (odds ratio [OR] 2.47; 95% confidence interval [CI] 1.22, 4.98; p = 0.01) and arousal domains (OR 2.85; 95%CI 1.34, 5.93; p = 0.005) and in total FSFI score (OR 2.01; 95%CI 1.45, 2.79; p < 0.001). The results remained statistically significant even after adjustment for smoking status.Conclusions: The study found evidence that women taking a combined EE/DRSP COCs for 3 months may have a worsening of sexual function as measured by FSFI.

Progestin isoforms provide different levels of protein S expression in HepG2 cells

IntroductionUse of combined oral contraceptives (COCs) results in acquired protein S (PS) deficiency, a well-established risk factor for venous thromboembolism (VTE). The risk of VTE due to COCs containing newer-generation progestins is double compared with COCs containing older-generation progestins, although there is little difference in estrogen contents between the generations. In contrast, progestin-only contraceptives do not confer an increased risk of VTE. In this study, we aimed to investigate how different isoforms of progestin in COCs affect the risk of VTE by measuring PS expression. Materials and methodsThe effect of progestin, levonorgestrel (LNG) or drospirenone (DRSP), on PS mRNA expression in HepG2 cells was measured using reverse transcription-quantitative PCR; PS level was determined using Western blot analysis. PROS1 promoter activity, PS mRNA stability, and de novo synthesis of PS mRNA were examined in HepG2 cells after treatment with progestin. Results and conclusionsIn the presence of progestins, PS mRNA and protein expressions were significantly upregulated in HepG2 cells due to the augmentation of de novo PS mRNA expression modulated by RNA polymerase II (Pol II), thereby facilitating PS transcription elongation. Moreover, the transcription elongation inhibitor blocked progestin-mediated de novo PS mRNA expression. Conversely, progestin did not affect PROS1 promoter activity and PS mRNA stability. Pol II elongation efficiency in the newer-generation progestin (DRSP) treatment was not as strong compared with older-generation progestin (LNG), suggesting the difference in VTE risk between COC generations.

Drospirenone plus estradiol and the risk of serious cardiovascular events in postmenopausal women

Objectives: To compare incidence rates of serious cardiovascular events, particularly arterial thromboembolic events (ATE), in users of hormone replacement therapy (HRT), particularly oral continuous combined preparations.Methods: Prospective, controlled cohort study with four arms: women using (1) drospirenone (DRSP)/estradiol, (2) other oral continuous combined HRT (HRTcc), (3) all other oral HRTs, and (4) non-oral HRT. The study population consisted of women aged 40+ years in seven European countries who were new users of HRT at the time of inclusion. All patient-reported outcomes of interest were validated by the treating physicians. A multifaceted, four-level follow-up procedure ensured low loss to follow-up rates. The final analysis is based on Cox regression models comparing the cohorts.Results: In total, 30 597 women were recruited by 1052 study centers. Follow-up reflects 101 715 woman-years of observation. Loss to follow-up was about 2.8%. Risk estimates for general serious adverse events were similar for all cohorts. Incidence rates for serious cardiovascular events were 98.4 (DRSP/estradiol) and 169.7 (HRTcc) per 10 000 woman-years. The corresponding incidence rates for ATE were 10.9 and 29.7 events per 10 000 woman-years with an adjusted hazard ratio of 0.5 (95% confidence interval 0.3–0.8). The initiation rate for antihypertensive treatment after start of HRT was substantially lower for women using DRSP/estradiol compared to the other cohorts.Conclusions: DRSP/estradiol is associated with general health risks similar to other oral and non-oral HRT but is probably associated with lower ATE risk.Clinical trial registration: NCT00214903, US National Library of Medicine.

Bleeding pattern and cycle control with estetrol-containing combined oral contraceptives: results from a phase II, randomised, dose-finding study (FIESTA)

ObjectivesThis study aims to assess vaginal bleeding patterns and cycle control of oral contraceptives containing estetrol (E4) combined with either drospirenone (DRSP) or levonorgestrel (LNG). Study designAn open-label, multicentre, randomised, dose-finding study lasting six cycles in healthy women aged 18–35 years was used. Four treatments (15 mg or 20 mg E4, combined with either 3 mg DRSP or 150 mcg LNG) were administered in a 24/4-day regimen. A marketed dosing regimen of estradiol valerate with dienogest (E2V/DNG) served as reference since it contains (like E4) a natural oestrogen. ResultsA total of 396 women were randomised, of whom 389 received study medication, and 316 completed the study. By cycle 6, the frequencies of unscheduled bleeding and/or spotting and absence of withdrawal bleeding were the lowest in the 15 mg E4/DRSP group (33.8% and 3.5%, respectively). In the E2V/DNG reference group, these frequencies were 47.8% and 27.1%, respectively. By cycle 6, the frequency of women with absence of withdrawal bleeding was <20% for all E4 treatment groups: 3.5–3.8% combined with DRSP and 14.0–18.5% combined with LNG. By cycle 6, unscheduled intracyclic bleeding was reported by <20% of women in the 20 mg E4/LNG group (18.9%) and in the 15 mg E4/DRSP group (16.9%). ConclusionThis study showed that, of the four treatment modalities investigated, the 15 mg E4/DRSP combination has the most favourable bleeding pattern and cycle control. ImplicationsDue to its favourable bleeding pattern and cycle control, the 15 mg E4/DRSP combination is the preferred combination for further phase III clinical development.

Effects of drospirenone on adhesion molecule expression and monocyte adherence in human endothelial cells

ObjectiveA major concern in hormone replacement therapy is the associated increased risk of cardiovascular diseases. A progestogen without the unfavorable effects on cardiovascular disease should be explored. Monocyte adhesion to endothelial cells is an important initial event in atherosclerosis. In this study, the effects of the alternative progestogen drospirenone (DRSP) on monocyte adhesion in human umbilical venous endothelial cells (HUVECs) were examined. Study designIn HUVECs treated with estrogens and progestogens, including DRSP and medroxyprogesterone acetate (MPA), the expression of the adhesion molecules E-selectin, P-selectin, ICAM-1, and VCAM-1 were examined by real-time PCR and using an enzyme-linked immunosorbent assay. A flow chamber system was used to investigate the effects of DRSP on U937 monocytoid cell adherence to HUVEC monolayers. All experimental data were compared using one-way Analysis of Variance. ResultsUpregulation of adhesion molecule mRNA or protein was not seen in HUVECs treated with DRSP alone or with 17β-estradiol+DRSP. DRSP alone, 17β-estradiol+DRSP or ethinylestradiol+DRSP did not increase the number of adherent monocytoid cells to HUVECs in the flow chamber system. However, MPA significantly enhanced the monocytoid cell adherence (P<0.05). ConclusionsDRSP did not increase the expression of adhesion molecules or monocytoid cell adherence to endothelial cells, indicating that DRSP could reduce the risk of atherogenesis caused by MPA. These results suggest that DRSP may be an alternative to MPA in hormone replacement therapy.

Drospirenone intake alters plasmatic steroid levels and cyp17a1 expression in gonads of juvenile sea bass

Drospirenone (DRO) is one of the most widely used progestins in contraceptive treatments and hormone replacement therapies. The pharmacokinetics and potential toxicological effects of DRO were investigated in juvenile sea bass (Dicentrarchus labrax) exposed through the diet (0.01–10 μg DRO/g) for up to 31 days. DRO was detected in the blood (4–27 ng/mL) of fish exposed to the highest concentration, with no significant bioaccumulation over time and no alteration of hepatic metabolizing enzymes, namely, CYP1A and CYP3A-catalysed activities and UDP-glucuronyltransferase (UGT). Pregnenolone (P5), progesterone (P4), 17α-hydroxyprogesterone (17P4), 17α-hydroxypregnenolone (17P5), androstenedione (AD) and testosterone (T) were determined in plasma and gene expression of cyp17a1, cyp19a1a and cyp11β analysed by qRT-PCR in gonads. The significant increase in plasmatic levels of 17P5, 17P4 and AD detected after 31 days exposure to 10 ng DRO/g together with the increased expression of cyp17a1 in females evidence the ability of DRO to alter steroid synthesis at low intake concentrations (7 ng DRO/day). However, the potential consequences of this steroid shift for female reproduction remain to be investigated.