Effects Of Combined Oral Contraceptives Research Articles

Combined estrogen-progestin oral contraceptives and female sexuality: an updated review.

Sexual side effects of combined oral contraceptives (COCs) have not been fully understood, but increasing evidence prompts broader risk/benefit evaluation and merits inclusion in counseling on contraceptive options. The study sought to explore the impact of combined estrogens-progestin oral contraceptives on components of female sexuality, including sexual desire, anatomic genitourinary changes, lubrication, orgasm, provoked vestibulodynia, well-being, body image, partner preference, and relationship stability. A literature review was performed between April 2023 and January 2024 exploring the association between combined oral contraceptive pills and sexual health. Although COCs decrease free testosterone, it is unclear if COCs affect sexual function, including desire. Antiandrogenic COCs do seem to have a negative effect on sexual arousal, lubrication, and orgasm. Provoked vestibulodynia may be related to early onset of COC use, low-estrogen pills, and antiandrogenic progestins. Emotional and sexual side effects are strong predictors of COC discontinuation. Longitudinal data indicate that using COCs when meeting and selecting a partner has implications on sexual satisfaction and relationship length. Analysis of data is complicated by various doses and forms of estrogen and progestin in COCs, which have changed over time. Lack of randomized placebo-controlled studies and heterogenicity in study design hampers generalized statements about the effects of COCs on sexual function. Despite these challenges, consideration of sexual dysfunction when presenting and prescribing hormonal contraception is essential for informed consent, shared decision making, and ensuring reliable contraceptive choices.

Continuous combined oral contraceptive use versus vitamin E in the treatment of menstrual migraine: rationale and protocol of a randomized controlled trial (WHAT!)

BackgroundCurrently, there is no evidence-based hormonal treatment for migraine in women. Several small studies suggest a beneficial effect of combined oral contraceptives, but no large randomized controlled trial has been performed. As proof of efficacy is lacking and usage may be accompanied by potentially severe side effects, there is a great need for clarity on this topic.MethodsWomen with menstrual migraine (n = 180) are randomly assigned (1:1) to ethinylestradiol/levonorgestrel 30/150 μg or vitamin E 400 IU. Participants start with a baseline period of 4 weeks, which is followed by a 12-week treatment period. During the study period, a E-headache diary will be used, which is time-locked and includes an automated algorithm differentiating headache and migraine days.ResultsThe primary outcome will be change in monthly migraine days (MMD) from baseline (weeks − 4 to 0) to the last 4 weeks of treatment (weeks 9 to 12). Secondary outcomes will be change in monthly headache days (MHD) and 50% responder rates of MMD and MHD.ConclusionsThe WHAT! trial aims to investigate effectivity and safety of continuous combined oral contraceptive treatment for menstrual migraine. Immediate implementation of results in clinical practice is possible.Trial registrationClinical trials.gov NCT04007874. Registered 28 June 2019.

The effects of dienogest and combined oral contraceptives on protein S-specific activity in endometriosis patients

ObjectiveOne serious side effect of combined oral contraceptives (COCs) is venous thromboembolism. Reduced activity in activated protein C-related coagulation pathways is attributable to low protein S activity in one-third of Japanese patients with deep vein thrombosis. Herer, we quantified the behavior of protein S-specific activity in response to dienogest (DNG) and COCs using the protein S-specific activity assay system to explore its potential utility as a thrombosis marker. Study DesignThis was a prospective cohort study. Female patients aged 20 – 49 years who were starting drug treatment for endometriosis using DNG or COCs were enrolled. Blood samples were taken before treatment and at the first, third, and sixth months of treatment. To analyze the primary endpoints, changes in total protein S antigen levels, total protein S activity, and protein S-specific activity from baseline to each time point were estimated using a linear mixed-effects model. All statistical analyses were performed in the SAS software version 9.4 (SAS Institute, Cary, NC). A two-sided P < 0.05 was considered statistically significant. Results64 patients took DNG and 34 patients took COCs. Protein S-specific activity did not change significantly from baseline in the six months after treatment started in either group. In the DNG group, total protein S activity and total protein S antigen levels increased slightly from baseline levels after the treatment. The means for total protein S activity and total protein S antigen levels in the COC group remained within reference limits, but they both decreased markedly in the first month and stayed low. Protein S-specific activity in four women remaind below the reference limit throughout the whole study period, suggesting they may have potential protein S deficiencies. ConclusionThe effects of DNG on protein S were negligible, though both total protein S activity and antigen levels decreased soon after COC treatment began and remained low. As there was no VTE event during the study, further studies with larger numbers of patients will be needed to confirm that protein S-specific activity can be a surrogate maker of VTE risk.

High-fat diet promotes coagulation and endothelial activation in Sprague Dawley rats: Short-term effects of combined oral contraceptives

BackgroundCombined oral contraceptives (COCs), use in individuals are associated with increased risk of thrombotic events. This highlights the significance of assessing the impact of COC on promoting coagulation and endothelial activation in high-fat diet (HFD)-fed Sprague Dawley rats. MethodsTwenty (20) five-weeks-old female Sprague Dawley rats weighing between 150 and 200g were subjected to both LFD and HFD-feeding for 8-weeks to determine its influence on basic metabolic status, hemostatic profile, hemodynamic parameters (blood pressure and heart rate), as well as selected biomarkers of coagulation (tissue factor and D-dimer) and endothelial activation (Von Willebrand factor and nitric oxide). Thereafter HFD-fed animals were treated with receive high dose combined oral contraceptive (HCOC) and low dose combine oral contraceptive (LCOC) for 6 weeks. ResultsOur results showed that beyond weight gain, HFD-feeding was associated with hyperglycemia, increased mean arterial pressure, and reduced nitric oxide levels when compared with LFD group (p<0.05). Interestingly, treatment with high dose of COC for 6-weeks did not significantly alter atherothrombotic markers (p>0.05). However, this study is not without limitation as regulation of these markers remains to be confirmed within the cardiac tissues or endothelial cells of these animals. ConclusionHFD-feeding orchestrate the concomitant release of pro-coagulants and endothelial activation markers in rats leading to haemostatic imbalance and endothelial dysfunction. Short-term treatment with COC shows no detrimental effects in these HFD-fed rats. Although in terms of clinical relevance, our findings depict the notion that the risk of CVD in association with COC may depend on the dosage and duration of use among other factors especially in certain conditions. However, additional studies are required to confirm these findings, especially long-term effects of this treatment within the cardiac tissues or endothelial cells of these animals in certain conditions relating to postmenopausal state.

Investigation of the effects of combined oral contraceptives used in patients with polycystic ovary syndrome on metabolic parameters

Investigation of the effects of combined oral contraceptives used in patients with polycystic ovary syndrome on metabolic parameters

The effect of hormonal contraceptive therapy on clinical laboratory parameters: a literature review.

Hormonal contraceptives (HC) are widely used among women in reproductive ages. In this review, the effects of HCs on 91 routine chemistry tests, metabolic tests, and tests for liver function, hemostatic system, renal function, hormones, vitamins and minerals were evaluated. Test parameters were differently affected by the dosage, duration, composition of HCs and route of administration. Most studies concerned the effects of combined oral contraceptives (COC) on the metabolic, hemostatic and (sex) steroids test results. Although the majority of the effects were minor, a major increase was seen in angiotensinogen levels (90-375 %) and the concentrations of the binding proteins (SHBG [∼200 %], CBG [∼100 %], TBG [∼90 %], VDBP [∼30 %], and IGFBPs [∼40 %]). Also, there were significant changes in levels of their bound molecules (testosterone, T3, T4, cortisol, vitamin D, IGF1 and GH). Data about the effects of all kinds of HCs on all test results are limited and sometimes inconclusive due to the large variety in HC, administration routes and dosages. Still, it can be concluded that HC use in women mainly stimulates the liver production of binding proteins. All biochemical test results of women using HC should be assessed carefully and unexpected test results should be further evaluated for both methodological and pre-analytical reasons. As HCs change over time, future studies are needed to learn more about the effects of other types, routes and combinations of HCs on clinical chemistry tests.

Abstract P3-03-27: Assessment of the proliferative activity of breast tissue after the administration of combined oral hormonal contraceptive, associated or not with estriol

Abstract The molecular mechanisms related to the breast cancer development are poorly understood, particularly those associated with estrogen. Evidence is mounting that developmental differences may influence the risk of cancer. However, understanding breast development, morphology and the biochemical factors that influence them is pertinent to study pre-malignant and malignant conditions that affect the breasts. Objective: To evaluate the proliferative activity of normal breast epithelium, through the c-myc expression, after the administration of combined oral hormonal contraceptive, associated or not with estriol. Retrospective double-blind study, in which the effect of combined oral contraceptives on the normal breast epithelium in women with fibroadenoma was evaluated. We analyzed 33 women In a cohort of 70 selected (37 excluded). The control group (1) received a compound containing levonorgestrel 0.15mg (LNG) and ethinylestradiol 0.03mg (EE), associated with 2mg of placebo (PLC) manufactured in the same capsule ingested daily for 21 days with an interval of 7 days, during four cycles. The study group (2) received a compound containing levonorgestrel 0.15 mg (LNG) and ethinylestradiol 0.03 mg (EE), associated with estriol 2 mg (E3) manufactured in the same capsule ingested daily for 21 days with an interval of 7 days, up to four cycles, when was proceeded the lumpectomy plus normal breast tissue sample. The UNIFESP-EPM Department of Pathology received the samples collected and fixed in 10% buffered formalin. We used an automation device to perform the Immunohistochemistry reactions, using c-myc antibodies, added DAB developer (diaminobenzidine) that provides a bright brown color that provides good contrast. We used conventional optical microscopy to read TMA slides. We considered positive the nuclei stained with dark brown in contrast to the blue negative to the c-myc reactions. We evaluated the epithelial areas at least five acinar units were present in the sample at 40X magnification. In the statistical analysis, the initial stages of consolidation as well as the analysis were performed in Software R (2020) and Rstudio (version 4.1), using the packages Tidyverse (2016), Psyco, SummaryTools, Janitor and DataExplorer. After verifying the assumptions of normality, independence and linearity, Student’s T test was performed for independent samples. An alpha of 0.05 was chosen for rejection of the null hypothesis, that is, a confidence interval of the test results of 95%. An effect size measure of the difference between the groups was also performed, called Cohen’s D; it ranges from -1 to 1, and the closer to 0, the smaller the effect size of the difference between the groups. Regarding the control group (30.30%) and the case group (69.70%). The table 2 presents the results for group 1 (COC + Placebo), while table 3 presents the results for group 2 (COC + Estriol). The T test was performed to verify a possible significant difference in the levels of cell proliferation in patients with or without Estriol. The normality was verified by the Shapiro-Wilk test, with data following a normal distribution (W = 0.901 and 0.96, p value &amp;gt; 0.3). The equitable variance was verified by the Levine test, which verified the equitable variance in both groups (F (1) = 0.24, p value = 0.62). A mean positive nucleus of 14 (SD = 10.65) was observed in the group of patients with contraceptive plus placebo and a mean of positive nuclei of 20.81 (SD = 9.88) in the group of patients with contraceptive plus Estriol. The ratio of positive nuclei to total was higher in the estriol group than in the control group. However, it was not possible to verify a significant difference in the two groups (T (14.57) = 1.3, p value = 0.215, d Cohen = 0.53). Cohen’s d pointed to a moderate difference effect (table 4). Table 2. Number of positive, negative and total normal epithelial cell nuclei in immunohistochemical investigation of c-myc antigens in Group 1 (COC + Placebo) (N = 10) Table 3. Number of positive, negative and total normal epithelial cell nuclei in immunohistochemical investigation of c-myc antigens in Group 2 (COC + Estriol) (N = 23) Table 4. Inferential results of the ratio of positive normal epithelial cell nuclei as a function of the control and case groups Citation Format: Osmar Pellegrini, Jr., Afonso Nazário, Angela Flavia L. Waitzberg. Assessment of the proliferative activity of breast tissue after the administration of combined oral hormonal contraceptive, associated or not with estriol [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-03-27.

Progesterone and contraceptive progestin actions on the brain: A systematic review of animal studies and comparison to human neuroimaging studies

In this review we systematically summarize the effects of progesterone and synthetic progestins on neurogenesis, synaptogenesis, myelination and six neurotransmitter systems. Several parallels between progesterone and older generation progestin actions emerged, suggesting actions via progesterone receptors. However, existing results suggest a general lack of knowledge regarding the effects of currently used progestins in hormonal contraception regarding these cellular and molecular brain parameters. Human neuroimaging studies were reviewed with a focus on randomized placebo-controlled trials and cross-sectional studies controlling for progestin type. The prefrontal cortex, amygdala, salience network and hippocampus were identified as regions of interest for future preclinical studies. This review proposes a series of experiments to elucidate the cellular and molecular actions of contraceptive progestins in these areas and link these actions to behavioral markers of emotional and cognitive functioning. Emotional effects of contraceptive progestins appear to be related to 1) alterations in the serotonergic system, 2) direct/indirect modulations of inhibitory GABA-ergic signalling via effects on the allopregnanolone content of the brain, which differ between androgenic and anti-androgenic progestins. Cognitive effects of combined oral contraceptives appear to depend on the ethinylestradiol dose.

The effect of combined oral contraceptives and Nexplanon on gastroesophageal reflux disease in premenopausal women: A nationwide database analysis.

Pregnancy, combined oral contraceptives (COC), and hormone replacement therapy have been reported to increase the risk of gastroesophageal reflux disease (GERD). To date, no study has evaluated the effect of Nexplanon, a commonly used progesterone-based contraceptive, on GERD. We aimed to determine the effect of Nexplanon and COC on GERD. We performed a population-based analysis using the IBM Explorys national database (1999-2021). The study group included premenopausal women, defined as women less than 50 years of age while excluding the diagnosis of menopause. The effect of Nexplanon and COC on GERD (at least 30 days after Nexplanon/COC was initiated) was assessed by comparing it to premenopausal women who were not on contraceptives. Foregut surgery, esophageal dysmotility disorders, hiatal hernia, and delayed gastric emptying were excluded. Odds ratios (OR) with 95% confidence intervals (CI) were calculated. A multivariate logistic regression analysis was conducted. A total of 23,299,470 patients were identified as being premenopausal, of which 47,260 were on Nexplanon and 5480 on COCs. As compared to premenopausal women with GERD on no contraceptives (n=565,880), 690 patients developed GERD at least 30 days after being on Nexplanon (OR=0.55, 95% CI [0.51-0.59], p < 0.001) and 280 developed GERD after COC (1.93, [1.71-2.18], p < 0.001). A multivariate analysis accounting for Caucasian race, obesity, smoking, alcohol use, and NSAIDs revealed that COC is an independent risk factor for GERD (1.16, [1.12-1.20], p < 0.001), and Nexplanon was protective against GERD (0.90, [0.89-0.92], p < 0.001). Hydralazine was used as a control medication for data reliability. A total of 8420 patients developed GERD after initiating hydralazine, which was not statistically nor clinically significant (OR=1.02, 95% CI [0.99-1.04], p=0.08) when compared to those not on contraceptives. Combined oral contraceptives is an independent risk factor for GERD, while Nexplanon has a limited protective effect. Further studies are needed to confirm the different effects on GERD of these two contraceptives.

Effect of combined oral contraceptives with estrogen identical to natural estrogen on the metabolic profile and body composition in females during the menopausal transition

Aim. To study the effect of combined oral contraceptives (COC) with estrogen identical to natural estrogen on the metabolic profile and body composition in females during the menopausal transition.&#x0D; Materials and methods. Females in the menopausal transition who needed contraception were divided into two groups. Group 1 (19 patients) received COCs containing estradiol valerate/dienogest (E2V/DNG) with a dynamic dosing regimen; Group 2 (19 patients) received monophasic COCs containing 17-estradiol/nomegestrol acetate (E2/NOMAC) for 6 months. Blood pressure (BP), parameters of carbohydrate and lipid metabolism, leptin, adiponectin, C-reactive protein, uric acid, and body composition by dual-energy X-ray absorptiometry were assessed initially and after the 6 months of therapy.&#x0D; Results. No significant changes in weight and body composition after 6 months of COC use were found in both groups. COCs with E2V/DNG had no significant effect on BP and all assessed metabolic parameters. Females taking COCs with E2/NOMAC showed increased fasting glucose of 4.85 (0.43) and 5.30 (0.37) mmol/L (p=0.002), insulin of 4.97 (2.35) and 8.82 (4.67) U/mL (p=0.012), NOMA index of 1.06 (0.54) and 1.88 (0.75); p=0.010 compared to baseline. However, the parameters remained within the reference values.&#x0D; Conclusion. COCs containing estrogens identical to natural estrogens do not affect body composition and have no significant adverse effect on BP and metabolic parameters in females during the menopausal transition, indicating that the use of these agents is acceptable from the perspective of their metabolic effects in this group of patients.

Combined oral contraceptives and mental health: Are adolescence and the gut-brain axis the missing links?

Combined oral contraceptives (containing synthetic forms of estradiol and progestins) are one of the most commonly used drugs among females. However, their effects on the gut-brain axis have not been investigated to a great extent despite clear evidence that suggest bi-directional interactions between the gut microbiome and endogenous sex hormones. Moreover, oral contraceptives are prescribed during adolescence, a critical period of development during which several brain structures and systems, such as hypothalamic-pituitary–gonadal axis, undergo maturation. Considering that oral contraceptives could impact the developing adolescent brain and that these effects may be mediated by the gut-brain axis, further research investigating the effects of oral contraceptives on the gut-brain axis is imperative. This article briefly reviews evidence from animal and human studies on the effects of combined oral contraceptives on the brain and the gut microbiota particularly during adolescence.

Combined oral contraceptives containing estradiol valerate vs ethinylestradiol on coagulation: A randomized clinical trial.

Contraceptives containing ethinylestradiol (EE) induce changes in the coagulation system and are associated with a risk of venous thromboembolism. However, studies comparing the effects of combined oral contraceptives containing EE and low-potency estrogens (ie, estradiol [E2 ] and estradiol valerate [EV]) on coagulation biomarkers are limited. This study represents secondary outcomes of a randomized trial comparing combined oral contraceptives containing EV + dienogest (DNG), EE + DNG, and DNG alone on selected coagulation biomarkers. We could compare the specific effects of the different estrogen components owing to the inclusion of preparations containing the same progestin. We enrolled 59 healthy, 18- to 35-year-old, non-smoking women, of whom three discontinued. The participants were randomly allocated to 9 weeks of continuous treatment with EV 2mg + DNG 2-3mg (n= 20), EE 0.03 mg + DNG 2mg (n= 20), or DNG 2mg (n= 19). Blood samples were collected at baseline and after 9 weeks. We assessed coagulation in vitro by thrombin generation using the Calibrated Automated Thrombogram. Thrombin generation was evaluated by lag time, time to thrombin peak, thrombin peak, and endogenous thrombin potential in response to tissue factor (1pm). In vivo coagulation assessment was based on levels of prothrombin fragment 1+2 (F1 +2) (thrombin generation) and D-dimer (fibrin turnover). NCT02352090. Lag time and time to thrombin peak remained unaltered after exposure to EV + DNG, whereas EE + DNG shortened both lag time (mean percentage change -24%, 95% confidence interval [CI] -32% to -15%; p< 0.01) and time to thrombin peak (-26%, 95% CI -37% to -16%; p< 0.01). EV + DNG induced lower thrombin peak and endogenous thrombin potential than EE + DNG (peak; +45%, 95% CI 22%-67% vs +147%,95% CI 96%-198%; p< 0.01, and endogenous thrombin potential; +26%, 95% CI 15%-38% vs +64%, 95% CI 51%-76%; p< 0.01). Median F1 +2 levels remained unchanged with EV + DNG (p= 0.22) but increased within normal ranges with EE + DNG (from 152 pmol/L, 95% CI 127-206]pmol/L to 194 pmol/L, 95% CI 149-250 pmol/L, p= 0.04). The within-group change in D-dimer levels was not significant in any of the groups. DNG alone did not affect these biomarkers. Both in vitro and in vivo thrombin generation was lower after exposure to EV + DNG compared with EE + DNG. The lower thrombin generation measures after treatment with EV + DNG indicate less enhancement of coagulation potential and suggest that EV may be favorable to EE as a component of combined oral contraceptives.

Counteracting side effects of combined oral contraceptives through the administration of specific micronutrients.

The occurrence of side effects related to the use of combined oral contraceptives (COCs) - or even the fear of them - often affects patients' compliance and their quality of life. Such adverse effects include both physical and psychological alterations. Therapies based on COCs are related to lower levels of vitamins and minerals, including vitamins B, C and E, zinc, magnesium, and selenium. This review gathers scientific evidence about the effectiveness of the administration of specific micronutrients to address nutritional needs and recover adverse conditions. We reviewed literature searching through different databases (MEDLINE, Scopus, Google Scholar). We used different keywords, including micronutrients, COCs, side effects, B vitamins, vitamin C, vitamin E, vitamin D, zinc, magnesium, selenium and Centella Asiatica. We narrowed the search down to English literature, including both preclinical and clinical studies. The outcome of database search was to highlight beneficial effects of specific micronutrients on the evaluated side reactions. Based on the collected evidence, dietary supplementations of specific micronutrients, whose depletion occurs during COC treatments, have significant beneficial effects. By acting on different aspects and pathways, such supplementation prevents and counteracts discomforts and side effects related to COC treatments. Considering the wide use of OCs, taking appropriate dietary supplements could be an effective approach in clinical practice, tailoring therapies and improving both safety and tolerability.

Renin-Angiotensin-Aldosterone System in Women Using Combined Oral Contraceptive: A Systematic Review.

To describe the effects of combined oral contraceptives (COC) on the renin-angiotensin-aldosterone system (RAAS). This is a systematic review according to the criteria of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), registered in PROSPERO under the ID: CRD42020200019. Searches were performed between August 2020 and December 2021, in the following databases: Medline via Pubmed, Cochrane Central Library, Scientific Electronic Library Online, and Latin American and Caribbean Literature in Health Sciences via Virtual Health Library. The effects of the combined oral contraceptive on plasma renin activity values, plasma renin values, angiotensinogen values- also known as plasma renin substrate- angiotensin, and/or aldosterone values. A total of 877 studies were selected and, of these, 10 articles met the eligibility criteria and were included in this review. Data were combined through qualitative synthesis and included in a spreadsheet previously prepared by the authors. The collected samples ranged from 18 to 137 participants, totaling 501 women aged between 18 and 49 years throughout all studies. The studies showed increased activity of plasma renin, plasma renin substrate, angiotensin II, and aldosterone in this population. The findings of this study suggest that the COC promotes greater activation of the RAAS. Supporting the idea that its use is related to an increased risk of cardiovascular events, including systemic arterial hypertension.

Estradiol Valerate vs Ethinylestradiol in Combined Oral Contraceptives: Effects on the Pituitary-Ovarian Axis.

Limited studies have compared the effects of combined oral contraceptives (COCs) containing natural estrogens and synthetic ethinylestradiol (EE) on reproductive hormones. To compare estradiol valerate (EV) + dienogest (DNG), EE + DNG, and DNG alone (active control) on levels of follicle stimulating hormone (FSH), luteinizing hormone, anti-Müllerian hormone (AMH), ovarian steroids, sex hormone binding globulin (SHBG), and the free androgen index (FAI). This spin-off study from a randomized trial enrolled 59 healthy, 18 to 35-year-old ovulatory women, outpatients at Helsinki and Oulu University Hospitals, Finland, who were randomized to EV 2 mg + DNG 2-3 mg (n = 20); EE 0.03 mg + DNG 2 mg (n = 20); and DNG 2 mg (n = 19) for 9 weeks. Blood samples were drawn at baseline, and at 5 and 9 weeks. Age and BMI were comparable between groups; 3 women discontinued. EV + DNG suppressed FSH by -27% (-51% to -3%) (median [95% CI]) vs EE + DNG, -64% (-78 to -51), P = 0.04, but AMH levels decreased similarly by -9% (-18 to -0.1) vs -13% (-28 to 0.2), P = 0.38, respectively. EV + DNG increased SHBG levels by 56% (30% to 82%) and EE + DNG by 385% (313% to 423%), P < 0.001. Total testosterone decreased by 16% (-27% to -5%) in the EV + DNG group but it did not decrease in the EE + DNG group, whereas the FAI decreased by -39% (-54% to -25%) vs -72% (-78% to -67%), P < 0.001. DNG alone did not induce changes in any of these parameters. Compared with EE + DNG, treatment with EV + DNG resulted in milder pituitary downregulation and reduced induction of hepatic SHBG synthesis-potentially carrying more beneficial health effects.

Abstract P2-11-18: Weekly evaluation of α estrogen and progesterone receptors in women´s breast epithelium after oral combined hormonal contraceptive use for one month

Abstract Introduction: The increased risk of breast cancer is the most controversial and most feared adverse effect of combined oral contraceptives (COC) by women. The mechanisms by which COC would act on the breast parenchyma leading to its increased incidence, are not yet well known. Objectives: To calculate and compare α estrogen receptor (ERα) and progesterone receptor (PR) expression in the mammary epithelium in the first, second, third and fourth weeks of patients who do not use COC (natural cycle) and those who use one cycle of COC composed of 30 µg ethinyl estradiol (EE) and 150 µg levonorgestrel (LNG). Casuistic and Methods: A retrospective study with paraffin blocks of 118 women from February 2001 to February 2004. At the time, women were included in the pre-menopause who had a breast lump with the triple diagnosis of positive benignity and eumenorrheic during the last six months. The study project was analyzed and approved by the Research Ethics Committee of UNIFESP-EPM, under number CEP 1182/06. The patients underwent excision of the breast lumps and adjacent normal breast tissue fragments which were fixed in 10% buffered formalin. 31 patients were excluded and 87 patients were analyzed. The patients were divided into two groups: group A (with COC) consisted of 42 women who used an COC cycle composed of 30μg of EE and 150μg of LNG, group B (without COC) consisted of 45 women with natural cycles. The immunohistochemical reaction was performed in an automation device and the following antibodies were used: ERα antibody clone SP1 titer 1:500 and PR antibody clone PgR636 titer 1:400. The histological slides were read using conventional optical microscopy. After identifying the epithelial areas, 7 fields with 40X magnification were evaluated. Statistical analysis for parity was performed using Fisher's exact test. At age the Students t-Test was applied. ERα and PR counts were evaluated in the Generalized Estimation Equation (EEG) model. In order to compare the total ERα and PR counts by evaluation and group moments, we used the Analysis of Variance (ANOVA) and the Kolmogorov-Smirnov test. Statistical analyzes were performed using the programs SPSS 20.0 and STATA 12. For all statistical tests the significance level of 5% (p ≤ 0.05) was adopted. Results: The control group (without COC) had a higher mean age of 23.7 ± 5.9 years compared to the study group (with COC) with a mean age of 20.5 ± 5.1 years. Regarding parity, the study group (with COC) had 83.9% of nulliparous versus 73.3% in the control group (without COC). From the EEG model a statistically significant mean difference in ERα expression was observed in the fourth week in the study group (with COC) compared to the control group (without COC) with p &amp;lt;0.001. The comparison of PR expressions in the control group (without COC) in the fourth week or in the late luteal phase (LLP) with the ERα expressions, also in the fourth week (LLP) of the control group (without COC) the mean PR expression was higher and statistically significant than ERα expression with p &amp;lt;0.001. The group of women using COC showed higher average percentages of ERα (p &amp;lt;0.001) and PR (p &amp;lt;0.001) when compared to women in the control group (without COC). Conclusions: The average of expressions of the ERα and PR in users of an COC cycle composed of 30 µg EE and 150 µg LNG higher percentages of ERα (p &amp;lt;0.001) and PR (p &amp;lt;0.001) when compared to women from the control group (without COC). The ERα expression in the study group (with COC) in the fourth week (pause) was higher than the ERα expression in the fourth week (LLP) of the control group (without COC), a statistically significant difference (p &amp;lt;0.001). The expression PR in the fourth week of the control group (without COC) or LLP was higher than the ERα and this difference was statistically significant (p &amp;lt;0.001). Citation Format: Weekly evaluation of α estrogen and progesterone receptors in women´s breast epithelium after oral combined hormonal contraceptive use for one month [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-11-18.

Сравнение эффективности применения инозитолов и комбинированных оральных контрацептивов для коррекции метаболических, эндокринных и клинических параметров пациенток с синдромом поликистозных яичников

The use of a combination of myoinositol and D-chiroinositol in a ratio of 5:1 (MI/DCI 5:1), manganese and folic acid appears promising for the correction of androgen-dependent dermopathy, regulation of the menstrual cycle, restoration of ovulation in patients planning pregnancy, as well as for improving endocrine and metabolic parameters, carbohydrate and lipid metabolism in patients with polycystic ovary syndrome (PCOS). Objective. To compare the effects of combined oral contraceptives (COCs) and combination of MI/DCI 5:1, manganese and folic acid on endocrine, metabolic and clinical parameters in patients with PCOS. Patients and methods. A prospective open-label clinical trial included 129 patients with PCOS. Patients in group 1 (A, n = 63) were prescribed COCs with antiandrogenic activity containing ethinyl estradiol 20 μg/drospirenone 3 mg; patients in group 2 (B, n = 66) were prescribed the combination of MI/DCI 5:1, manganese and folic acid for 6 months. Lifestyle modifications were also recommended for all patients: physical activity and diet therapy. Results. Low serum androgen levels were observed in both groups. The use of COCs resulted in a more significant reduction in hirsutism according to the Ferriman-Gallwey score and clinical manifestations of acne. Administration of the combination of MI/DCI 5:1 showed good results in improving carbohydrate and lipid metabolism in patients with PCOS. Thus, in group B there was a significant reduction in glucose levels (4.9 ± 0.3 vs. 5.2 ± 0.5 mmol/L, p &lt; 0.01) and fasting insulin (12.1 ± 5.3 vs. 22.2 ± 4.9 mmol/L, p &lt; 0.01), HOMA and CARO indices. No changes in carbohydrate metabolism were observed during COCs administration, but there was an increase in cholesterol levels (6.0 ± 0.7 vs. 5.7 ± 0.5 mmol/L, p &lt; 0.05), low-density lipoproteins (LDL) (3.9 ± 0.4 vs. 3.5 ± 0.6 mmol/L, p &lt; 0.05), and atherogenic coefficient (AC). Lipid profile parameters in group B improved significantly from baseline by reducing cholesterol (5.1 ± 0.6 vs. 5.6 ± 0.6 mmol/L, p &lt; 0.05), triglycerides (1.5 ± 0.4 vs. 1.8 ± 0.3 mmol/L, p &lt; 0.05), and LDL (2.7 ± 0.5 vs. 3.6 ± 0.8 mmol/L, p &lt; 0.01). Diet therapy and administration of the combination of MI/DCI 5:1, manganese and folic acid resulted in a 4.4% decrease in waist circumference and a 4.8% decrease in body mass index (BMI). In contrast, the COCs group showed a 2.1% increase in waist circumference and a 4.7% increase in BMI, which may be related to an increased appetite. In group B, the regularity of menstrual cycle in patients with PCOS was also analyzed. After 6 months of therapy, a regular cycle was observed in 40% of patients vs. 11% of patients at baseline with a mean duration of 33.3 ± 9.4 days (p &lt; 0.05). Conclusion. Lifestyle modification with the combination of MI/DCI 5:1, manganese and folic acid is effective for the correction of endocrine, metabolic, and clinical profile in patients with PCOS and appears to be a promising new alternative to COCs regardless of reproductive planning. Key words: polycystic ovary syndrome, myoinositol, D-chiroinositol, hyperandrogenism, insulin resistance, hirsutism, acne

Obituary: Samuel J. Machin MB ChB FRCP FRCPath, 26 March 1949 – 2 October 2021

On Saturday 2 October, we were saddened to learn of the death of Professor Samuel (Sam) Machin after a short, final illness. Sam was a larger than life character who had a certain vision about how haematology should be and strived to achieve modernization. Through his distinguished career, he was involved with many of the National and International societies and committees involved in haematology and standardization. Sam studied medicine at Sheffield University from 1966 to 1971. He received his haematology training at Manchester Royal Infirmary before taking a Senior Registrar post at the Middlesex Hospital Medical School. In 1979, he joined Jos Vermylen and others at the Department of Vascular and Haemostasis Research, KU, Leuven. It was here where he commenced his career in haemostasis and thrombosis, researching on platelets, prostacyclin and haemolytic uraemic syndrome. Returning to London, he was appointed Consultant Haematologist (the youngest at the time to achieve that post in the UK) and worked with Professor Jimmie Stewart. Sam’s career progressed with his achievements leading to his appointment as Professor of Haematology at The Middlesex and later University College London (UCL). A large number of scientists and junior doctors received expert training in the Department, many obtaining MD and/or PhD. Almost without exception, trainees whom Sam mentored and supported have gone on to become consultants, professors, heads of department and divisions in hospitals, universities, the National Blood Service and industry. He took an active role in organizing the UCL Haemostasis Training Course, which helped haematologists from many parts of the world to obtain Fellowship of the Royal College of Pathologists. In 1981, Sam founded what was to become the Haemostasis Research Unit at UCL and directed research in many aspects of haemostasis and thrombosis. His primary areas were platelet function, thrombotic thrombocytopaenia, antiphospholipid syndrome and the prothrombotic effects of combined oral contraceptives. He was also interested in laboratory automation and set up an analyser and reagent evaluations unit that studied most new haematology and coagulation systems. He understood the need to communicate and encouraged staff to present their data at conferences, and he co-authored over 400 peer-reviewed publications. Sam worked tirelessly in supporting the interests of many societies and organizations. He was President of the British Society for Haemostasis and Thrombosis (2001-03) and British Society for Haematology (2005-07), serving as treasurer from 1994 to 2000. He chaired the British Committee for Standardisation in Haematology, UK NEQAS Haematology Steering Committee (2006-11) and the International Council for Standardization in Haematology (2007-20). He was Treasurer of the International Society for Thrombosis and Haemostasis (ISTH) for the 2003 congress in Birmingham and Vice Chairman of the ISTH Scientific Standards Committee. In 2007, Sam led the reorganization and modernization of the International Council for Standardization in Haematology and remained as Chair of this body until 2020. His enthusiasm and energy resulted in the publication of more than 30 peer-review publications on standardization in haematology, including many guidance and recommendation documents. He was a supporter of laboratory haematology as a discipline. He encouraged the late Berend Houwen to develop further meetings on “Technical Innovations in Laboratory Hematology,” which later led to the formation of the International Society for Laboratory Hematology, of which Sam became a board member. He served on the Editorial Board of this journal (International Journal of Laboratory Hematology) and remained an active reviewer (even saying just 2 weeks prior to his death that he would like to receive more manuscripts). Sam enjoyed playing and watching sport, being passionate about cricket, hockey and rugby league. A kind and generous man, although sometimes controversial because he liked to speak his mind. He had a way of cutting through bureaucracy, side stepping obstacles and getting things done. He is survived by his wife Jean, son Robert and daughters Clare and Rowena as well as 5 grandchildren.

The effect of combined oral contraceptives containing drospirenone and ethinylestradiol on serum levels of amino acids and acylcarnitines.

Metabolome variations have long been associated with normal hormonal fluctuations, and similar effects, related to the use of early generation synthetic hormones as a means of contraception, have also been identified. We investigated the serum amino acid and acylcarnitine profiles induced by the use of combined oral contraceptives (COCs) consisting of Ethinylestradiol (EE) and a 4th generation progestin, Drospirenone (DRSP). Gas chromatography mass spectrometry and liquid chromatography with tandem mass spectrometry was used to identify and quantify the serum amino acids and acyl carnitine levels in 24 controls, 25 DRSP/20EE users and 26 DRSP/30EE users. Of the 26 amino acid compounds measured, 13 showed significant variations in abundance between the control and COC user groups. Although none of the 21 acylcarnitine compounds detected were statistically significant with regards to group variations, a trend, related the EE concentration, was observed. The detected metabolome disparities corresponded to that identified for earlier generation COCs, all pointing toward increased oxidative stress levels in the user groups. These findings suggest that the clinical complications associated with these COCs could, to some extent, be alleviated by the simultaneous use of antioxidants. The study also highlights the role that targeted metabolomics could play in the elucidation of the underlying mechanisms of drug-induced severe effects.

Coagulation Kinetics in Adolescent Females Initiating Combined Oral Contraceptives

Objectives: The objective of this pilot study was to evaluate the effect of combined oral contraceptives (COC) on rotational thromboelastometry (ROTEM®) and Technothrombin®TGA (thrombin generation assay) coagulation kinetics, as a surrogate marker of thrombotic risk, in adolescent females. The epidemiology of risk factors associated with contraception-related venous thromboembolism (VTE) in adolescents is not well defined. Estrogen contained in COC produces activated protein C resistance thus increasing the risk of thrombosis. The risk of COC-related VTE is significantly impacted by duration of COC use. The highest risk of COC-related VTE is during the first 6 to 12 months in first-time users. Furthermore, the risk of contraception-related VTE is higher for obese women as compared with non-obese women. Recent evidence found that endogenous thrombin potential (ETP) increased during COC initiation, but have not followed users longitudinally.Methods: This longitudinal cohort included adolescents, ages 12-21 years, initiating COC containing 35 mcg ethinyl estradiol/0.25 mg norgestimate. Balanced recruitment was utilized to strive for equal numbers of obese and non-obese subjects and varied gynecologic age (i.e. years from menarche). Exclusion criteria included personal/family history of thrombophilia or venous thromboembolism, personal history of bleeding diatheses, contraindication to COC, tobacco use, hemoglobin < 10 g/dL, and anti-platelet or anticoagulant medication use. Citrated whole blood samples were collected at baseline (pre-COC), 1, 3, 6, and 12 months for coagulation studies (TGAÒ and ROTEMÒ) and FSH suppression to document COC adherence. TGA parameters included: ETP and peak thrombin production. ROTEMÒkinetic parameters evaluated included: clotting time (CT); viscosity amplitude at 10 & 20 minutes (A10 & A20); and maximum clot firmness (MCF). Changes in parameters were explored over 6 months of COC exposure for coagulation kinetics and 12 months for ETP.Results: Interim analyses included 15 subjects out of a planned 30 total (86.7% White; mean age 16.8 ± 2.8 years; mean BMI 25.1 kg/m2, BMI range 16.2-43.3 kg/m2, 33.3% obese). Post-COC, mean ETP was elevated above baseline (3176.8 nM*min) as early as 1 month and was highest at 6 months (3869.6 & 3890.8 nM*min; p<0.05) (Figure 1A).Mean peak thrombin production was increased from baseline to 6 months (179.5 vs 224.7 nM; p<0.05). From baseline to 3 months, there was a significant (p<0.05) increase in mean A10 (48.0 vs. 52.1 mm), A20 (53.8 vs. 58.6 mm), and MCF (54.0 vs. 58.6 mm) (Figures 1B,1C).There was a significant decrease in mean CT from baseline to 6 months (252.6 vs. 210.6 seconds; p<0.05).Conclusions: After COC initiation, adolescents demonstrated hypercoagulable alterations in TGA and all ROTEM® kinetic parameters. These alterations were evident as early as 1 month but continued to increase over the next 5 months. Continued study will assess if hypercoagulable alterations persist at 12 months. Further study will explore the impact of obesity status at COC initiation on thrombotic risk, as assessed by these global coagulation assays. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.