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Drugs Jul 2022Estetrol/drospirenone is a combined oral contraceptive (COC) with a plant-synthesised foetal oestrogen (estetrol) and a well-established progestin (drospirenone). In... (Review)
Review
Estetrol/drospirenone is a combined oral contraceptive (COC) with a plant-synthesised foetal oestrogen (estetrol) and a well-established progestin (drospirenone). In preclinical models, estetrol has lower binding affinity for the oestrogen receptor-α (ER-α) in contrast to estradiol and has antagonistic properties against membrane ER-α in several tissues, including the breast, while retaining agonistic activity on receptors located in the nucleus. The low oestrogenicity of estetrol may potentially contribute to reduced thrombotic risk. Estetrol/drospirenone was an effective contraceptive in phase II and III clinical trials, with regular and predictable bleeding cycles maintained in the majority of women. Estetrol/drospirenone was generally well-tolerated with metrorrhagia reported as the most common treatment-related adverse event, which is consistent with other COCs. Cases of migraines with aura (or severe migraines), deep vein thrombosis, hyperkalaemia and depression were rarely reported during the phase III trials. Overall, estetrol/drospirenone is an effective and generally well-tolerated COC, with a potentially reduced risk of thrombosis.
Topics: Androstenes; Clinical Trials, Phase III as Topic; Contraceptives, Oral, Combined; Estetrol; Female; Humans
PubMed: 35781795
DOI: 10.1007/s40265-022-01738-8 -
Contraception Apr 2021To evaluate the effect on endocrine and metabolic parameters of a new combined oral contraceptive (COC) containing estetrol (E4) and drospirenone (DRSP). (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
To evaluate the effect on endocrine and metabolic parameters of a new combined oral contraceptive (COC) containing estetrol (E4) and drospirenone (DRSP).
STUDY DESIGN
Randomized, open-label, controlled, 3-arm, parallel study. Healthy subjects received either E4 15 mg/DRSP 3 mg (E4/DRSP) (n = 38), or ethinylestradiol (EE) 30 µg/levonorgestrel (LNG) 150 µg (n = 29), or EE 20 µg/DRSP 3 mg (n = 31) for 6 treatment cycles. Median percentage change from baseline to cycle 3 and to cycle 6 were evaluated for endocrine parameters, liver proteins, lipid profile, and carbohydrate metabolism.
RESULTS
At cycle 6, E4/DRSP treatment had less effect on gonadotropins (follicle stimulating hormone [FSH] +30.5%, luteinizing hormone [LH] -7.5%) compared to EE/LNG (FSH -84.0%, LH -92.0%) and EE/DRSP (FSH -64.0%, LH -90.0%). With E4/DRSP increases in total cortisol (+26.0%) and cortisol binding globulin ([CBG] (+40.0%) were less compared to EE/LNG (cortisol +109.0%, CBG +152.0%) and EE/DRSP (cortisol +107.0%, CBG +140.0%). Liver proteins, except CRP, increased, but the effect was less pronounced with E4/DRSP for angiotensinogen (+75.0%) compared to EE/LNG (+170.0%) and EE/DRSP (+206.5%) and for sex hormone binding globulin ([SHBG] +55.0%), compared to EE/LNG (+74.0%) and EE/DRSP (+251.0%). E4/DRSP had minimal impact on lipid parameters; the largest effect was observed for triglycerides (+24.0%), which was less compared to EE/LNG (+28.0%) and EE/DRSP (+65.5%). E4/DRSP had no effect on carbohydrate metabolism.
CONCLUSIONS
E4/DRSP treatment has limited effects on endocrine and metabolic parameters. The effects on gonadotropins, cortisol, CBG, angiotensinogen, SHBG and triglycerides were less pronounced compared to EE-containing products.
IMPLICATIONS STATEMENT
Combining E4 15 mg with DRSP 3 mg resulted in a COC with a different metabolic profile in comparison to EE-containing products. The clinical relevance of these findings needs to be further assessed, using clinical endpoints to establish the safety profile of this new COC.
Topics: Androstenes; Contraceptives, Oral, Combined; Estetrol; Estrogens; Ethinyl Estradiol; Female; Humans; Levonorgestrel; Sex Hormone-Binding Globulin
PubMed: 33428907
DOI: 10.1016/j.contraception.2021.01.001 -
Women's Health (London, England) 2023The spironolactone derivative drospirenone is combined with ethinylestradiol or estetrol in combined oral contraceptives. Formulations with 17-β-estradiol are used to... (Review)
Review
The spironolactone derivative drospirenone is combined with ethinylestradiol or estetrol in combined oral contraceptives. Formulations with 17-β-estradiol are used to treat climacteric symptoms. A drospirenone-only formulation has been introduced for contraception. Here, the pharmacological properties of drospirenone, the impact of the different formulations on metabolic and laboratory parameters, and the resulting clinical implications are reviewed. Ethinylestradiol, an inhibitor of CYP metabolic enzymes, changes the pharmacokinetics of drospirenone, leading to a higher drospirenone exposure with ethinylestradiol/drospirenone compared to the drospirenone-only preparation. In addition, several metabolic alterations have been described. The impact of estetrol is less pronounced, and for 17-β-estradiol/drospirenone and drospirenone-only, decreased triglyceride and cholesterol levels were observed. Ethinylestradiol induces various pro-coagulatory factors, leading to hypercoagulability. The effect is significantly reduced with estetrol, and no influence was observed with the drospirenone-only preparation. The anti-mineralocorticoid activity of drospirenone seems to positively counteract the renin-angiotensin-aldosterone-system-activating action of ethinylestradiol. There is no influence on blood pressure with ethinylestradiol/drospirenone and estetrol/drospirenone formulations, while in clinical trials, a reduction has been observed with 17-β-estradiol/drospirenone and drospirenone-only. Anti-aldosterone activity via non-renal mineralocorticoid receptors is associated with cardiovascular health, while interactions with parathyroid hormone signaling impact bone structure and vascular calcification. Though the clinical relevance is unclear for drospirenone, data in this context are reviewed. To sum up, the advantages of drospirenone in hormonal contraception and treatment of menopausal symptoms have been demonstrated for all the formulations described here. Combination with estrogen confers benefits and risks, which must be considered.
Topics: Female; Humans; Progestins; Estetrol; Estrogens; Ethinyl Estradiol; Contraceptives, Oral, Combined; Estradiol
PubMed: 36744531
DOI: 10.1177/17455057221147388 -
Contraception Sep 2021To assess efficacy, cycle control, and safety of an oral contraceptive containing estetrol (E4) 15 mg and drospirenone (DRSP) 3 mg.
OBJECTIVE
To assess efficacy, cycle control, and safety of an oral contraceptive containing estetrol (E4) 15 mg and drospirenone (DRSP) 3 mg.
STUDY DESIGN
Women aged 16 to 50 years with a body mass index ≤35 kg/m enrolled in this multicenter, open-label, 13-cycle, phase 3 trial evaluating E4/DRSP in a 24-active/4-placebo regimen. Follow-up was scheduled at Cycles 2, 4, 7, and 10 and within 3 weeks of completing Cycle 13. Participants used daily diaries to record pill use and vaginal bleeding. We evaluated efficacy outcomes in women 16 to 35 years and bleeding patterns and safety (adverse events [AEs]) in all participants. We assessed overall and method-failure pregnancy rates using the Pearl index (PI) and life-table analysis. Scheduled bleeding included spotting or bleeding starting during the 4-day placebo period or first 3 days of the next cycle.
RESULTS
We enrolled 1864 women of whom 1674 were 16 to 35 years. Women 16 to 35 years had a PI of 2.65 (95% CI 1.73-3.88), method-failure PI of 1.43 (95% CI 0.7-2.39) and 13-cycle life-table pregnancy rate of 2.1%. Scheduled bleeding occurred in 82.9% to 87.0% of women per cycle; median duration was 4.5 days. Unscheduled bleeding decreased from 30.3% in Cycle 1 to 21.3% to 22.1% during Cycles 2 to 4 and remained stable (15.5% to 19.2%) thereafter. The most frequently reported AEs were headache (5.0%) and metrorrhagia (4.6%). One-hundred thirty-two (7.1%) women discontinued the study early for an AE, most commonly for metrorrhagia (0.9%) and menorrhagia (0.8%). No thromboembolic events occurred.
CONCLUSION
E4/DRSP is an effective oral contraceptive with a predictable bleeding pattern for most women and low AE rates.
IMPLICATIONS STATEMENT
A new oral contraceptive with a novel estrogen, estetrol, combined with drospirenone has efficacy and safety within the range of other available oral contraceptives. Large phase 4 studies will be needed to confirm if this combination is associated with an improved adverse event profile or lower thrombosis risk.
Topics: Androstenes; Contraceptives, Oral, Combined; Estetrol; Estrogens; Ethinyl Estradiol; Female; Humans; North America; Pregnancy
PubMed: 34000251
DOI: 10.1016/j.contraception.2021.05.002 -
Drugs in R&D Jun 2023Estetrol (E4) is the most recently described natural estrogen. It is produced by the human fetal liver during pregnancy and its physiological function remains unclear.... (Review)
Review
Estetrol (E4) is the most recently described natural estrogen. It is produced by the human fetal liver during pregnancy and its physiological function remains unclear. E4 is the estrogenic component of a recently approved combined oral contraceptive. It is also in development for use as menopausal hormone therapy. In the context of these developments, the pharmacological activity of E4, alone or in combination with a progestin, has been extensively characterized in preclinical models as well as in clinical studies in women of reproductive age and postmenopausal women. Despite the clinical benefits, the use of oral estrogens for contraception or menopause is also associated with unwanted effects, such as an increased risk of breast cancer and thromboembolic events, due to their impact on non-target tissues. Preclinical and clinical data for E4 point to a tissue-specific activity and a more selective pharmacological profile compared with other estrogens, including a low impact on the liver and hemostasis balance. This review summarizes the characterization of the pharmacological properties of E4 as well as recent advances made in the understanding of the molecular mechanisms of action driving its activity. How the unique mode of action and the different metabolism of E4 might support its favorable benefit-risk ratio is also discussed.
Topics: Female; Humans; Estetrol; Pharmacology, Clinical; Estrogens; Breast Neoplasms
PubMed: 37133685
DOI: 10.1007/s40268-023-00419-5 -
Journal of Lipid Research Apr 2020Analyzing global steroid metabolism in humans can shed light on the etiologies of steroid-related diseases. However, existing methods require large amounts of serum and...
Analyzing global steroid metabolism in humans can shed light on the etiologies of steroid-related diseases. However, existing methods require large amounts of serum and lack the evaluation of accuracy. Here, we developed an LC/MS/MS method for the simultaneous quantification of 12 steroid hormones: testosterone, pregnenolone, progesterone, androstenedione, corticosterone, 11-deoxycortisol, cortisol, 17-hydroxypregnenolone, 17-hydroxyprogesterone, dehydroepiandrosterone, estriol, and estradiol. Steroids and spiked internal standards in 100 μl serum were extracted by protein precipitation and liquid-liquid extraction. The organic phase was dried by evaporation, and isonicotinoyl chloride was added for steroid derivatization, followed by evaporation under nitrogen and redissolution in 50% methanol. Chromatographic separation was performed on a reverse-phase PFP column, and analytes were detected on a triple quadrupole mass spectrometer with ESI. The lower limits of quantification ranged from 0.005 ng/ml for estradiol to 1 ng/ml for cortisol. Apparent recoveries of steroids at high, medium, and low concentrations in quality control samples were between 86.4% and 115.0%. There were limited biases (-10.7% to 10.5%) between the measured values and the authentic values, indicating that the method has excellent reliability. An analysis of the steroid metabolome in pregnant women highlighted the applicability of the method in clinical serum samples. We conclude that the LC/MS/MS method reported here enables steroid metabolome analysis with high accuracy and reduced serum consumption, indicating that it may be a useful tool in both clinical and scientific laboratory research.
Topics: Analytic Sample Preparation Methods; Blood Chemical Analysis; Chromatography, Liquid; Female; Humans; Limit of Detection; Metabolomics; Pregnancy; Solvents; Steroids; Tandem Mass Spectrometry
PubMed: 31964762
DOI: 10.1194/jlr.D119000591 -
BJOG : An International Journal of... Jan 2022To assess the contraceptive efficacy, bleeding pattern and safety of a combined oral contraceptive containing estetrol (E4) 15 mg and drospirenone (DRSP) 3 mg.
OBJECTIVES
To assess the contraceptive efficacy, bleeding pattern and safety of a combined oral contraceptive containing estetrol (E4) 15 mg and drospirenone (DRSP) 3 mg.
DESIGN
Multicenter, open-label, phase 3 trial.
SETTING
Sixty-nine sites in Europe and Russia.
POPULATION
Sexually active women aged 18-50 years with regular menstrual cycles and body mass index ≤35 kg/m .
METHODS
E4/DRSP was administered in a 24 active/4 placebo regimen for up to 13 cycles. Visits were scheduled during Cycles 2, 4, 7 and 10 and after completing treatment during which adverse events (AEs) were collected. Participants recorded medication intake, vaginal bleeding/spotting, use of other contraceptive methods and sexual intercourse on a daily diary.
MAIN OUTCOME MEASURES
Pearl Index (PI) for women 18-35 years (overall and method-failure), bleeding pattern and AEs.
RESULTS
A total of 1553 women aged 18-50 years, including 1353 from 18 to 35 years old, received the study medication. PI was 0.47 pregnancies/100 woman-years (95% CI 0.15-1.11); method failure PI was 0.29 pregnancies/100 woman-years (95% CI 0.06-0.83). Scheduled bleeding/spotting occurred in 91.9-94.4% of women over Cycles 1 to 12 and lasted a median of 4-5 days per cycle. The percentage of women with unscheduled bleeding/spotting episodes decreased from 23.5% in Cycle 1 to <16% from Cycle 6 onwards. The most common AEs were headache (7.7%), metrorrhagia (5.5%), vaginal haemorrhage (4.8%) and acne (4.2%). One treatment-related serious AE was reported, a lower extremity venous thromboembolism. One-hundred and forty-one (9.1%) women discontinued study participation because of treatment-related adverse events.
CONCLUSION
E4/DRSP provides effective contraception, a predictable bleeding pattern and a favourable safety profile.
TWEETABLE ABSTRACT
A phase 3 trial with E4/DRSP shows high contraceptive efficacy, a predictable bleeding pattern and favourable safety profile.
Topics: Adolescent; Adult; Contraceptives, Oral, Combined; Estetrol; Europe; Female; Humans; Metrorrhagia; Middle Aged; Russia; Young Adult
PubMed: 34245666
DOI: 10.1111/1471-0528.16840 -
Current Neurology and Neuroscience... Jan 2024Given the potential for exogenous hormones to influence risk and course of MS, this narrative review aims to summarize current knowledge from observational and... (Review)
Review
PURPOSE OF REVIEW
Given the potential for exogenous hormones to influence risk and course of MS, this narrative review aims to summarize current knowledge from observational and interventional studies of exogenous hormones in humans with MS.
RECENT FINDINGS
Large randomized clinical trials for combined oral contraceptives and estriol both show modest effect on inflammatory activity, with the latter showing potential neuroprotective effect. After fertility treatment, large actively treated cohorts have not confirmed any elevated risk of relapse. Preclinical data suggest that androgens, selective estrogen receptor modulators (SERMs), and selective androgen receptor modulators (SARMs) may be neuroprotective but clinical data are lacking. Gender affirming treatment, particularly estrogen in trans-women, could possibly be associated with elevated risk of inflammation. For women with MS entering menopause, hormone therapy appears safe during the appropriate menopausal window, but its long-term effects on neuroprotection are unknown. Exogenous hormones, used in varied doses and for diverse indications, have variable effects on MS risk, inflammatory activity, and neuroprotection. Large randomized trials are needed before it is possible to determine the true effect of exogenous hormones in a condition as complex as MS.
Topics: Humans; Female; Multiple Sclerosis; Estrogens; Menopause
PubMed: 38102502
DOI: 10.1007/s11910-023-01326-7