Drospirenone Research Articles (Page 1)

Clinical characteristics of polycystic ovary syndrome (PCOS) (menstrual irregularities, obesity, anovulation, etc.), occur together with a series of conditions at skin level like seborrhea, acne, hirsutism, and androgenetic alopecia. Estroprogestins (EPs) are recognized as the most powerful therapy to treat hyperandrogenism and/or hyperandrogenemia and regularize menstrual cycle. This review includes the most relevant publications about the effects of EPs in PCOS women published between 1995 and 2025. According to the available data, EPs composed by an anti-androgenic progestin appear the most suitable to reduce the hyperandrogenic manifestations of PCOS. More specifically, cyproterone acetate (CPA), drospirenone (DRSP) and dienogest (DNG) associated with 20-30 μg of ethinylestradiol (EE) seem to be the most effective compounds for the management of androgen excess. As the benefit risk/ratio of the association EE/CPA is less favorable, the use of EPs with other antiandrogenic progestins could be more appropriate to treat PCOS patients, also from a metabolic point of view. In conclusion, an aware choice of the most adequate and tolerable EP formulation according to the pharmacological profile and individual characteristics of PCOS patient is essential to opportunely customize the treatment of androgen excess.

Combined oral contraceptives (COCs) are commonly prescribed for the prevention of pregnancy, as well as numerous other non-contraceptive health reasons. COCs act by suppressing the natural hormonal fluctuations of the menstrual cycle that result in ovulation. No studies have investigated the effects of COC use on endogenous estrogen biotransformation and the production of estrogen metabolites. This is important since imbalances in hormone biotransformation (e.g., inefficient methylation by catechol O-methyltransferases; COMT) are implicated in the initiation of breast cancer through the generation of genotoxic metabolites (i.e., estrogen quinones) and reactive oxygen species (ROS), and the depletion of vital antioxidants and metabolic cofactors. Here, we quantified the urinary levels of various estrogen precursors and metabolites in healthy young women who were using COCs containing drospirenone (DRSP) and ethinyl estradiol (EE) (n = 24) and controls (n = 25) via liquid chromatography–tandem mass spectrometry (LC‒MS/MS). In addition, we analysed several circulatory intermediates of the methylation cycle that are linked to the methylation of catechol estrogens via LC‒MS/MS. We found that free urinary estradiol (E2) and estrone (E1) were significantly lower, while 2-methoxyestrone (2-MeOE1) levels were significantly higher in COC users. Excretion of some metabolites including 16-hydroxylation pathway metabolites, glutathione conjugates, and DNA-adducts were also lower in COC users, although total hormone and metabolite excretion levels were not significantly different. Estrone metabolite ratios were higher in COC users, including 2&4-MeOE1:E1, 2&4-OHE1:E1, E1-3-sulphate: E1, and E1-3-glucuronide: E1. There was a positive correlation between 2-hydroxyestrogen and 2-methoxyestrogen levels in controls but not in COC users. In addition, the serum betaine and dimethylglycine (DMG) levels, as well as the betaine: choline ratio, were reduced in COC users, whereas the levels of choline and serine and the DMG: betaine ratio were significantly increased. DMG levels positively correlated with methoxyestrogens and methoxyestrogen: hydroxyestrogen ratios in COC users, while S-adenosylmethionine (SAM) negatively correlated with 2-MeOE2. Our data suggests that the use of EE/DRSP increases the flux of endogenous hormones into the hormone biotransformation pathway, resulting in increased conversion of estrogens (especially E1) into conjugated, catechol, and methylated estrogens but that the latter is limited by methyl-group donor availability. Interestingly, the increased oxidation of estrogens in COC users does not result in increased DNA-adduct formation.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-16892-8.

According to the FDA Guidance for Industry on Clinical Drug Interaction (DDI) Studies with Combined Oral Contraceptives (COCs), sponsors are expected to conduct dedicated clinical DDI studies if in vitro findings suggest weak or moderate CYP3A induction, while concomitant use of COCs with strong inducers should be avoided. The guidance further suggests that a negative DDI result for drospirenone (DRSP) may be extrapolated to other progestins that are less sensitive to CYP3A modulation, such as levonorgestrel (LNG). This approach assumes that DDI-mediated changes in exposure directly translate into clinical efficacy across progestins. To evaluate the validity of this assumption, we established a quantitative link between dose, exposure, and response (Pearl Index [PI] and ovulation rate [OR]) via an integrated model-based meta-analysis, physiologically based pharmacokinetic, and pharmacokinetic/pharmacodynamic (PK/PD) modeling and simulation approach using data from 51 clinical studies in 36,040 women receiving LNG or DRSP. COCs containing LNG and DRSP were selected because they represent clinically relevant progestins at the lower and the upper end of the fraction metabolized via CYP3A4. The results of our analysis show a moderate correlation (Pearson's r = 0.52, 95% CI 0.46-0.58, P<0.001) between PI and OR, which enables the use of OR as an ethically measurable endpoint, even at subtherapeutic doses/exposures, to predict efficacy outcomes. They further show that DDI-induced changes in exposure do not directly translate into clinical response. Therefore, DDIs with COCs should be interpreted in a PK/PD rather than a PK-only context. The quantitative framework developed in this study can serve as the scientific basis to do so.

To evaluate the efficacy and safety of 4 mg of drospirenone (DRSP), a progestin-only pill (POP), for contraception in Japanese women. This was a multicenter, open-label, single-arm study. The dosing period of DRSP was 13 cycles, each lasting for 28 days. In one cycle, 4 mg of DRSP was administered orally once daily for the first 24 days, followed by a placebo for 4 days. Data from 276 subjects were analyzed, with a total of 3319 DRSP exposure cycles. Pregnancy occurred in one subject. The overall Pearl Index [95% CI] was 0.39 [0.01, 2.18], and the cumulative pregnancy rate [95% CI] was 0.40% [0.06, 2.81]. Of the 276 subjects, 273 (98.9%) experienced treatment-emergent adverse events (TEAEs) and 264 (95.7%) experienced adverse drug reactions. All TEAEs were mild or moderate, with no severe events. The most common TEAE was intermenstrual bleeding (irregular uterine bleeding) (89.5%). Although 31.9% of the subjects had risk factors for venous thromboembolism (VTE), no VTE-related TEAEs were observed. The incidence of unscheduled bleeding [95% CI] across all cycles was 91.6% [87.7, 94.3]. DRSP, the first POP in Japan, is effective and safe as a contraceptive in Japanese women. It provides a new contraceptive option for Japanese women, including those at risk of VTE for whom combined oral contraceptives are contraindicated.

ABSTRACTBackground:DRSP (drospirenone) is a progestin that has antiandrogenic and anti-mineralocorticoid activity. When used combined with estradiol (E2), drospirenone helps in relieving symptoms of menopause.Aim:To assess the effects of continuous use of oral drospirenone/estradiol on lipid profile, body weight, and BP to minimize cardiovascular risk in females with early menopause.Methods:The present study assessed 128 menopausal females with a mean amenorrhoeic period, mean BMI, and mean age of 2.46 ± 2.44 years, 25.06 ± 2.92 kg/m2, and 49.17 ± 4.60 years, respectively. Effects of combined oral drospirenone/estradiol in 1 mg dose were assessed on lipid levels, hormones, anthropometric data, heart rate, and BP variability in early menopausal females with untreated stage 1 hypertension. All subjects were assessed before and after 12 months of therapy.Results:DRSP/E2 resulted in significant BP reduction during 6 and 12 months of therapy, with systolic and diastolic BP reduction in -4.50 to -8.50 and -4.0 to -5.0 mm Hg, respectively. No significant change in nocturnal 24-hour BP, significant day-time and night-time reduction at follow-up in HR, significant reduction in BMI, apolipoprotein B, and cholesterol were observed.Conclusions:The present study concludes that continuous and long-term therapy using oral drospirenone/estradiol leads to a significant reduction in cardiovascular diseases and better BP control.

BackgroundProgestogens, synthetic analogues of progesterone, are widely used in clinical practice for contraception, hormone replacement therapy, and the management of gynecological disorders. Understanding the specific impacts of different progestogens on the renin-angiotensin-aldosterone system (RAAS) is crucial due to their potential effects on cardiovascular and renal outcomes.ObjectiveThis systematic review aims to synthesize existing research on the effects of various progestogens on the RAAS and associated clinical outcomes.MethodsWe conducted a comprehensive search of databases up to the search date, including randomized controlled trials (RCTs), cohort studies, case-control studies, cross-sectional studies, and qualitative studies. The NIH Study Quality Assessment Tool for Controlled Intervention Studies was used to evaluate the quality of the included studies. Data extraction and quality assessment were performed independently by two reviewers, with discrepancies resolved through discussion.ResultsForty-two studies on drospirenone (DRSP) were the most extensively investigated, showing either decreased or unchanged blood pressure (BP), mostly unchanged serum sodium, and an increased risk of hyperkalemia only in patients with mild renal impairment. Sixteen studies on norethindrone (NET/NETA) presented conflicting results on BP and a higher risk of hyperkalemia. Other progestogens, such as levonorgestrel (LNG) and medroxyprogesterone acetate (MPA), showed varied effects on RAAS parameters. Notably, changes in plasma renin activity (PRA), serum aldosterone, and angiotensin II levels were inconsistent across different progestogens and study designs.ConclusionThe effects of progestogens on the RAAS are complex and varied, influenced by the type of progestogen, dosage, and combination with estrogen. While some progestogens like DRSP may offer benefits in BP management with minimal electrolyte disturbances, others like NET/NETA might require more careful monitoring due to their associated risks. These findings highlight the importance of personalized medicine approaches in the use of progestogens, tailored to individual patient characteristics and specific hormonal profiles. Further research with standardized methodologies is needed to clarify these effects and guide clinical practice.Trial registrationThis review was prospectively registered with PROSPERO.

Background A prolonged release combined oral contraceptive (COC) pill, containing 2 mg dienogest (DNG)/0.02 mg ethinylestradiol (EE) in a 24 + 4 daily dosing regimen has recently been approved in Europe. Objective To determine if this COC impacts coagulation and fibrinolytic factors in comparison to an immediate release COC containing 3 mg drospirenone (DRSP)/0.02 mg EE. Method Forty-four patients received the novel product, and forty-seven the comparator (immediate release formulation) during nine complete cycles. Coagulation and fibrinolytic parameters were evaluated: activated protein C resistance ratio, Antithrombin III (AT III), C-reactive protein, Factor VII, Factor VIII, and D-Dimer. Results Compared to baseline, at the end of the study both groups displayed significantly higher mean values for AT III: 1.06 mg/mL (standard deviation [SD], 95% CI, 0.98–1.15) for the DNG/EE formulation and 1.04 mg/mL (SD 95% CI, 0.96–1.12) for the comparator (p = 0.0006 and p = 0.0009, respectively). D-dimer showed a non-significant slight reduction in the DNG/EE group, from 276.62 ng/mL (SD, 95% CI, 228.92–334.26) before treatment to 243.98 ng/mL (SD, 95% CI, 192.45–309.31) ng/mL after treatment. Contrarily, the comparator displayed a non-significant rise in D-dimer values from 246.46 ng/mL (SD, 95% CI, 205.44–295.66) ng/mL to 275.30 ng/mL (SD, 95% CI 219.21–345.75; p = 0.4520). All other parameters showed no significant differences before and after the treatment for both groups. Conclusion The COC 2 mg DNG/0.02 mg EE was not associated with any meaningful changes in the analyzed coagulation and fibrinolytic parameters indicating that a prolonged release formulation does not impact on these factors. Clinical trial registry EudraCT: 2019-0018-77-97

Combined oral contraceptives (COC)s are the contraceptive method of choice for millions of women worldwide. In this study, we aimed to investigate the effects of COC administration, composed of 17α-ethinylestradiol (EE2) and drospirenone (DRSP), on obesity, glucose tolerance, and hepatic steatosis in female mice. Eighty-day-old <italic>Swiss</italic> female mice were fed either a standard diet (SD) or a high-fat diet (HFD) and daily received, via gavage, 0.2 mL of distilled water (CTL-SD and CTL-HFD groups) with or without COC (COC-SD and COC-HFD groups) for 65 days. COC administration attenuated body weight and adiposity gains and prevented glucose intolerance induced by HFD in COC-HFD females. These effects were accompanied by the upregulation of <italic>Prdm16</italic> and <italic>Ucp-1</italic> genes in the brown adipose tissue (BAT) of COC-HFD mice. These females also exhibited a lower hepatic steatosis score than CTL-HFD mice; however, their liver parenchyma showed an increased number of inflammatory foci, and up-regulation of the <italic>Il-1β</italic> gene. Thus, COC administration in female mice attenuated obesity development induced by HFD, possibly through modulation of BAT function, while the increased hepatic expression of the pro-inflammatory cytokine IL-1β suggests that COC exacerbated HFD-induced liver inflammation.

Drospirenone (DROP) is a highly effective, low-toxicity, safe new generation progestin that counteracts estrogen-related sodium retention, is well tolerated, and has a positive effect on premenstrual syndrome (PMS). However, the low water solubility of DROP and its chemical instability resulted in low bioavailability. In this study, we developed a two-step delivery system to enhance drospirenone's solubility and stability. We prepared a drospirenone liposome complex to optimize the encapsulation process and achieve an encapsulation efficiency of (84.9 ± 0.73) %, with an 878-fold increase in solubility under optimal conditions. To address the instability of high drug-loading liposomes, we immobilized the drospirenone liposome inclusion complex using a cellulose-based hydrogel. The system achieved uniform loading of liposomes in the hydrogel, as confirmed by SEM and FTIR analysis. 0.5g hydrogel can be loaded with up to 96.48mg drospirenone, and the encapsulation efficiency is (80.4 ± 1.17%). It was indicating the potential for wider application of drospirenone with enhanced water solubility and improved stability. At the same time, it also provides support for sustained-release systems or large dose drug delivery.

Background Dienogest (DNG) 2 mg/ethinylestradiol (EE) 0.02 mg is the first low-dose combined oral contraceptive (COC) with a prolonged-release formulation that allows stable plasma concentrations and has high contraceptive efficacy (Pearl index: 0.2). The aim of this trial was to determine the bleeding profile of this contraceptive compared to an immediate release formulation. Methods This prospective double-blind randomised controlled trial evaluated the bleeding patterns of DNG 2 mg/EE 0.02 mg compared with immediate-release drospirenone (DRSP) 3 mg/EE 0.02 mg in a 24/4-day regimen over nine cycles (randomisation ratio, 5:2). Participants recorded scheduled and unscheduled bleeding/spotting data using an electronic diary. A non-inferiority analysis for the proportion of participants with unscheduled bleeding/spotting was prespecified for Cycles 2–6. Safety, including adverse events, were monitored throughout the trial. Results Seven-hundred six and 288 participants received DNG/EE and DRSP/EE, respectively. Scheduled bleeding patterns per each 28-day cycle were similar in both groups. During Cycles 2–6, the proportion of participants with unscheduled bleeding/spotting was significantly lower in the DNG/EE group (50.5% [280/574] than in the DRSP/EE group (72.8% [171/235]]; treatment difference 22.3% [95% CI 15.9, 28.6%]; p < 0.0001). A low proportion of participants discontinued the trial due to bleeding disorders (1.7% and 0.7%, respectively). The safety profiles were similar for both treatments. Conclusions The prolonged-release DNG 2 mg/EE 0.02 mg offers a significant decrease in unscheduled bleeding/spotting compared with an immediate-release COC, DRSP/EE, combined with high contraceptive efficacy and a very low adverse event profile.

We compared the efficacy of 4 mg drospirenone (DRSP) progestin-only pills (POPs) versus combined oral contraceptive pills (COCs) containing 0.02 mg of ethinyl estradiol (EE) and 0.075 mg of gestodene (GS) in ovulation inhibition and inducing unfavorable cervical mucus changes using a delayed-starting approach. This randomized controlled trial involved 36 participants aged 18–45 years. The major outcomes included ovulation inhibition assessed using the Hoogland and Skouby score, and cervical mucus permeability, assessed using the modified World Health Organization score. The results demonstrated ovulation inhibition rates of 77.8% for the EE/GS group and 88.9% for the DRSP group. The risk ratio and absolute risk reduction were 0.50 (95% confidence interval [CI]: 0.10, 2.40) and − 0.11 (95% CI: − 0.35, 0.13), respectively, satisfying the 20% non-inferiority margin threshold. The median time to achieve unfavorable cervical mucus changes was comparable between the DRSP (3 days, interquartile range [IQR]: 6 days) and EE/GS (3.5 days, IQR: 4 days) groups. However, the DRSP group had a higher incidence of unscheduled vaginal bleeding (55.56% vs. 11.11%; p = 0.005). DRSP-only pills, initiated on days 7–9 of the menstrual cycle, were non-inferior to EE/GS pills in ovulation inhibition. However, they exhibited delayed unfavorable cervical mucus changes compared to the standard two-day backup recommendation.Clinical trial registration: Thai Clinical Trials Registry (TCTR20220819001) https://www.thaiclinicaltrials.org/show/TCTR20220819001.

Continuous wavelet transform and integration of discrete wavelet transform with principal component analysis and fuzzy inference system for the simultaneous determination of ethinyl estradiol and drospirenone in combined oral contraceptives

Evaluating the toxicity of estetrol, 17α-ethinylestradiol, and their combination with drospirenone on zebrafish larvae: A behavioural and proteomic study

Combined oral contraceptives, comprising of both an oestrogen and a progestin component, are released in aquatic environments and potentially pose a risk to aquatic wildlife by their capacity to disrupt physiological mechanisms.In this study, the endocrine disruptive potential of two mixtures, 17α-ethinylestradiol (EE2), a synthetic oestrogen, or estetrol (E4), a natural oestrogen, with the progestin drospirenone (DRSP) have been characterised in three generations of zebrafish, according to an adapted Medaka Extended One Generation Reproduction Test. Zebrafish (Danio rerio) were exposed to a range of concentrations of EE2/DRSP and E4/DRSP (∼1×, ∼3×, ∼10× and ∼30× predicted environmental concentration, PEC). Survival, growth, hatching success, fecundity, fertilisation success, vitellogenin (VTG), gonad histopathology, sex differentiation, and transcriptional analysis of genes related to gonadal sex steroid hormones synthesis were assessed.In the F0 generation, exposure to EE2/DRSP at ∼10 and ∼30× PEC decreased fecundity and increased male VTG concentrations. The highest concentration of EE2/DRSP also affected VTG concentrations in female zebrafish and the expression of genes implicated in steroid hormones synthesis. In the F1 generation, sex determination was impaired in fish exposed to EE2/DRSP at concentrations as low as ∼3× PEC. Decreased fecundity and fertility, and abnormal gonadal histopathology were also observed. No effects were observed in the F2 generation. In contrast, E4/DRSP induced only minor histopathological changes and an increase in the proportion of males, at the highest concentration tested (∼30× PEC) in the F1 generation and had no effect on hatching success of F2 generation.Overall, this study suggests that the combination E4/DRSP has a more favourable environmental profile than EE2/DRSP.

Use of serum evaluation of contraceptive and ovarian hormones to assess reduced risk of pregnancy among women presenting for emergency contraception in a multicenter clinical trial

Enhancing the solubility and dose delivery of drospirenone through oxidized regenerated cellulose hydrogel compound with liposome system

Use of the Drospirenone-Only Contraceptive Pill in Adolescents with Endometriosis

Background: Combined oral contraceptives (COCs) work mostly by preventing the pre-ovulatory gonadotropin surge, but the action of COCs on spontaneous episodic and GnRH (gonadotropin-releasing hormone)-induced LH (luteinizing hormone) release has been poorly evaluated. Oral contraceptives are known to act on the spontaneous hypothalamic–pituitary functions reducing both GnRH and gonadotropin release and blocking ovulation. Aim: To evaluate spontaneous and GnRH-induced LH release during both phases of the menstrual cycle or under the use of the contraceptive pill. Methods: A group of 12 women, subdivided into two groups, volunteered for the study. Group A (n = 6, controls) received no treatments, while Group B (n = 6) received a 21 + 7 combination of ethinyl-estradiol (EE) 30 µg + drospirenone (DRSP) 3 mg. Both groups were evaluated twice: Group A during follicular and luteal phases, Group B during pill assumption and during the suspension interval, performing a pulsatility test, GnRH stimulation test, and hormonal parameters evaluation. Spontaneous and GnRH-induced secretory pulses were evaluated, as well as the instantaneous secretory rate (ISR). Results: COC treatment lowered LH and FSH (follicle stimulating hormone) levels significantly if compared to the follicular phase of spontaneous cycles. During the suspension interval, hormone levels rapidly rose and became comparable to those of the follicular phase of the control group. The LH pulse frequency under COC administration during the suspension interval was similar to that observed during the follicular phase (2.6 ± 0.3 pulses/180 min and 2.3 ± 0.2 pulses/180 min, respectively). The GnRH-induced LH peaks were greater in amplitude and duration than those observed after ISR computation in both groups. The GnRH-induced LH release during the luteal phase of the control subjects was higher than in the follicular phase (51.2 ± 12.3 mIU/mL and 14.9 ± 1.8 mIU/mL, respectively). Conversely, subjects under COC showed a GnRH-induced LH response similar during COC and during the suspension interval. Conclusions: Our data support that the EE + DRSP preparation acts on both spontaneous pulsatile release and GnRH-induced LH release during the withdrawal period of the treatment, and that after 5–7 days from the treatment suspension, steroidal secretion from the ovary is resumed, such as that of androgens. This suggests that in hyperandrogenic patients, a suspension interval as short as 4 days might be clinically better.

Background: combined oral contraceptives (COCs) are one of the most popular methods of contraception. Apart from pregnancy prevention, it has proven other positive non-contraceptive effects. However, there are cases of acne vulgaris (AV) manifestation during COCs intake or its course worsens, which can lead to treatment refusing. Aim: to study the COCs effect (20 μg ethinyl estradiol (EE) and 3 mg drospirenone (DRSP)) on the skin condition of young women with a regular menstrual period. Patients and Methods: a prospective study was performed, which included 18 female patients of reproductive age (mean age 20.67±0.46 y.o.) with a regular menstrual period who sought medical advice to select a contraceptive. Of these, 11 had mild to moderate AV manifestations. The female patients were recommended to take DRSP-containing COConce daily before bedtime from the 1st day of the menstrual period for 28 straight days (1 period) — a total of 6 periods. Before the treatment initiation, as well as 3 and 6 months after the COCs intake start, the skin condition and indicators of the Acne-specific Quality of Life Questionnaire (Acne-QoL) of female patients with AV were evaluated. Results: the number of female patients without AV or with improvement after 3 and 6 months of treatment was 12 (66.67%) and 18 (100%), respectively. Compared with the baseline, there was a statistically significant decrease in Acne-QoL from 68 (63-80) to 40 (36-50) and 5 (10- 17) after 3 and 6 months, respectively (p&lt;0.05). The good tolerability of DRSP-containing COC was also noted. Adverse events that were independently eliminated and did not require drug withdrawal were recorded in two (11.1%) cases. Conclusion: the use of DRSP-containing COC (20 μg EE and 3 mg DRSP) in women with a regular menstrual period improves skin condition (reduces the amount and severity of AV) and reduces Acne-QoL. KEYWORDS: acne, drospirenone, ethinyl estradiol, reproductive period, regular menstrual period, acne vulgaris, questionnaire, quality of life. FOR CITATION: Saprykina L.V., Narimanova M.R. Drospirenone-containing contraceptive effect on the skin condition in women with a regular menstrual period. Russian Journal of Woman and Child Health. 2024;7(1):41–44 (in Russ.). DOI: 10.32364/2618-8430-2024-7-1-6.

Venous thromboembolism is a serious safety concern in women using combined oral contraceptives; ethinyl estradiol (EE) is widely used as an estrogen. Estetrol (E4) is a native estrogen with selective tissue activity and exclusively produced by the fetal liver. This study used a multicenter, randomized, open-label, active-controlled, parallel-group design to evaluate the effects of E4 combined with drospirenone (DRSP) on coagulation and fibrinolysis in Japanese patients with endometriosis. Participants were randomized to receive either E4 15 mg/DRSP 3 mg or EE 20 µg/DRSP 3 mg for 12 weeks. E4/DRSP and EE/DRSP were administered orally once a day in a cyclic regimen, ie, 24-day active use followed by a 4-day hormone-free period, and a flexible extended regimen, respectively, and blood coagulation and fibrinolysis markers were measured. The effect on coagulation and fibrinolysis was considerably less in the E4/DRSP group than in the EE/DRSP group. Major anticoagulant proteins, protein S (free, total) and tissue factor pathway inhibitor (free), were reduced following EE/DRSP treatment. Consequently, thrombin generation determined by the activated protein C sensitivity ratio was increased by approximately 4-fold in the EE/DRSP group than in the E4/DRSP group. Eventually, the fibrinolysis cascade was triggered to compensate for disturbed coagulation, and D-dimer levels were 4.7-fold higher in the EE/DRSP group than in the E4/DRSP group. This study demonstrated that the effect of E4/DRSP on the blood coagulation and fibrinolysis cascades was significantly less than that of EE/DRSP in participants with endometriosis, a disease of women of advanced and reproductive age (jRCT2080225090, https://jrct.niph.go.jp/en-latest-detail/jRCT2080225090).