Oral Contraceptive Formulations Research Articles

Lower reporting of venous thromboembolisms events with natural estrogen-based combined oral contraceptives compared to ethinylestradiol-containing pills: A disproportionality analysis of the Eudravigilance database

ObjectivesPharmacovigilance data analysis can accelerate the identification of drug-related safety signals or reassure on the safety profile. This study evaluates the venous thromboembolism (VTE) risk of newer combined oral contraceptive (COC) formulations with natural estrogens, such as estradiol (E2) and estetrol (E4), using data from the EudraVigilance database. Study designWe conducted a disproportionality reporting rate analysis of VTE events associated with various COC formulations by extracting individual case reports from EudraVigilance database up to July 28, 2024. The study compared the proportionality reporting rate between natural estrogen-based COCs (E2 and E4) and conventional synthetic estrogen-based COCs (ethinylestradiol [EE]), with a comparison to EE-levonorgestrel. ResultsThe analysis revealed that COCs containing natural estrogens exhibited significantly lower proportionality reporting rates for thrombotic events compared to EE-based COCs. Specifically, E4-drospirenone (E4-DRSP) showed the lowest proportionality reporting rate (0.12), similar to progestin-only pills. EE-DRSP had the highest proportionality reporting rate (2.25), suggesting an increased thrombotic risk. ConclusionsThe study supports the safer thrombotic profile of natural estrogen-based COCs, particularly E2 and E4 formulations, over synthetic estrogen-based COCs containing EE. These findings support the hypothesis that E2- and E4-based pills are safer than EE-based pills, aligning with a shift toward safer contraceptive options in clinical practice. ImplicationsNatural estrogens such as E2 and E4 may emerge as safer alternatives to synthetic estrogens like EE, particularly when combined with progestins like DRSP. This multilevel evidence underscores the importance of evidence-based prescribing practices to enhance patient safety and minimize thrombotic risks associated with COC use.

The benefits of estetrol addition to drospirenone for contraception

Ethinylestradiol and drospirenone combined oral contraceptive formulations have been marketed for >20 years. Drospirenone has antimineralocorticoid and anti-androgenic effects that may offer several health benefits. Recently, 2 new drospirenone-containing oral contraceptives entered the market, 1 as a progestin-only pill containing 4 mg drospirenone and the other as a combined oral contraceptive containing 15 mg estetrol and 3 mg drospirenone. Estetrol has a unique differential effect on nuclear and membrane estrogen α-receptors when compared with other estrogens, leading to low impact on the liver, breast, and hemostasis parameters and a beneficial effect on the endometrium, vagina, cardiovascular system, bone, and brain. Phase 3 clinical studies demonstrated that the Pearl Index (pregnancies per 100-woman-years) for drospirenone alone is 4.0 in the United States and 0.93 in the European Union and for the estetrol-drospirenone combination it is 2.65 and 0.44, respectively. Drospirenone alone demonstrates high rates of unscheduled bleeding and low rates of scheduled bleeding, whereas the estetrol-drospirenone combination demonstrates a predictable and regular bleeding profile for most users with a high stable rate of scheduled bleeding and a low rate of unscheduled bleeding, reported primarily as spotting only. The adverse event profiles and discontinuation rates owing to adverse events are comparable, and no clinically significant effects were observed on metabolic parameters with either product. Hemostatic assays for drospirenone do not fully evaluate all parameters although the testing that is available suggests negligible effects, whereas validated hemostatic assays demonstrate that the estetrol-drospirenone combination has limited impact on hemostasis. The introduction of 4 mg drospirenone and 15 mg estetrol with 3 mg drospirenone are valuable additions to the contraceptive market. Adding estetrol to 3 mg drospirenone provides advantages of contraceptive efficacy and a regular, predictable bleeding profile with minimal impact on hemostasis parameters.

(013) Estetrol Combined with Drospirenone: An Investigational Oral Contraceptive With A Selective Impact on Endocrine Parameters

Abstract Introduction Combined oral hormone contraceptive use is associated with decreased circulating androgens (Burrows LJ, et al. J Sex Med. 2012) and increased hormone binding globulins (Mawet M, et al. Eu J Cont Rep Hlth Care. 2015). Estetrol (E4) is a human-specific estrogen produced by the fetal liver, and has selective action in different tissues. The combination of E4 and Drospirenone (DRSP) was evaluated in a Phase-2 study to determine the potential effects on endocrine parameters. Objectives To evaluate the change from baseline in serum concentration of various endocrine and liver protein markers at cycle 3 and 6 in subjects receiving E4/DRSP and two comparison combined oral contraceptive (COC) formulations. Methods In this randomized, open-label, three-arm parallel study, participants received E4 15 mg /DRSP 3mg (n = 38), or ethinyl-estradiol (EE) 30 g/Levonorgestrel (LNG) 150 g (n = 29) or EE 20 g/DRSP 3 mg (n = 31) in a 24/4-day regimen of 6 consecutive, 28-day treatment cycles. Changes from baseline in serum total testosterone (TT), free testosterone (FT), androstenedione, dehydroepiandrosterone sulfate (DHEA-S), cortisol binding globulin (CBG), sex hormone binding globulin (SHBG), and thyroxine binding globulin (TBG) were determined at cycle 3 and 6. Potential differences between baseline and cycle 3 and 6 for all treatments, as well as pairwise comparisons of E4/DRSP and each of the other two formulations are considered statistically significant with an exploratory P-value < 0.05. Results TBG was significantly increased with EE/LNG (47% and 37%) and EE/DRSP (80% and 70%) at cycle 3 and 6. TBG was also increased significantly but to a lesser extent with E4/DRSP (27% and 17%). CBG increased at cycle 6 in all treatments. The increase in CBG was significantly greater with EE/LNG (152%) and EE/DRSP (140%) than that noted for E4/DRSP (40%). A significant increase in SHBG was observed at cycle 3 (240%) and 6 (251%) with EE/DRSP as compared to baseline or E4/DRSP (52% and 55%). At cycle 3, a significant decrease in TT was observed for E4/DRSP (35%), EE/LNG (40.5%), and EE/DRSP (41%). FT was significantly reduced at cycle 3 for E4/DRSP, EE/LNG, and EE/DRSP at 50%, 60%, and 75%, respectively. At cycle 6, a similar pattern of significant reductions in both TT and FT was observed with each treatment. Pairwise comparison, revealed no significant differences in TT and FT among groups. There were significant decreases in androstenedione at cycle 3 and 6, with E4/DRSP (32% and 31%), EE/LNG (44% and 49%), and EE/DRSP (40% and 40%). DHEA-S was significantly reduced from baseline at cycle 3 and 6 in all treatments. There was a significant difference in DHEA-S at cycle 6 with EE/DRSP (27%) compared to E4/DRSP (11%). Conclusions E4/DRSP had lower increases in hormone binding globulins compared to EE/LNG or EE/DRSP. Increases in SHBG were significantly higher for EE/DRSP than E4/DRSP. A decrease in TT and FT with E4/DRSP was not significantly different from EE/LNG or EE/DRSP. E4/DRSP had a significantly lower impact on DHEA-S levels than EE/DRSP. Disclosure Yes - Mithra Women's Health. Industry initiated, executed and funded study – Yes.

Effects of oral contraceptives on spatial cognition depend on pharmacological properties and phase of the contraceptive cycle.

The central nervous system effects of oral contraceptives (OCs) are not well-documented. In a set of 3 studies, we investigated a specific cognitive function, mental rotation, in healthy women currently using OCs for contraceptive purposes (n = 201) and in medication-free controls not using OCs (n = 44). Mental rotation was measured using a well-standardized and extensively validated psychometric test, the Vandenberg Mental Rotations Test (MRT). In an initial study (Study 1), current OC users (n = 63) were tested during the active or inactive phases of the contraceptive cycle in a parallel-groups design. Studies 2 and 3 were based on an archival dataset (n = 201 current OC users) that consisted of data on the MRT collected in real-time over a 30-year period and compiled for purposes of the present work. The OCs were combined formulations containing ethinyl estradiol (10-35 ug/day) plus a synthetic progestin. All 4 families of synthetic progestins historically used in OCs were represented in the dataset. Cognitive performance was evaluated during either active OC use (‘active phase’) or during the washout week of the contraceptive cycle (‘inactive phase’) when OC steroids are not used. The results showed a significant phase-of-cycle (POC) effect. Accuracy on the MRT was mildly diminished during the active phase of OC use, while scores on verbal fluency and speeded motor tasks were modestly improved. The POC effect was most evident in women using OCs that contained first- or second-generation progestins (the estrane family of progestins or OCs containing levonorgestrel), but not in women using OCs containing recently developed progestins and lower doses of ethinyl estradiol. Using independently established ratings of the estrogenic, androgenic, and progestogenic intensities of the different OC formulations, each brand of OC was classified according to its distinct endocrine profile. Multiple regression revealed that the effects of OC use on the MRT could be predicted based on the estrogenic strength of the contraceptives used. Estrogenic potency, not androgenic or anti-androgenic effects of the OC pill, may underlie the effects of OC usage on spatial cognition.

Oral contraceptive use by formulation and breast cancer risk by subtype in the Nurses' Health Study II: a prospective cohort study

Oral contraceptive use has been associated with a higher breast cancer risk; however, evidence for the associations between different oral contraceptive formulations and breast cancer risk, especially by disease subtype, is limited. This study aimed to evaluate the associations between oral contraceptive use by formulation and breast cancer risk by disease subtype. This prospective cohort study included 113,187 women from the Nurses' Health Study II with recalled information on oral contraceptive usage from 13 years of age to baseline (1989) and updated data on usage until 2009 collected via biennial questionnaires. A total of 5799 breast cancer cases were identified until the end of 2017. Multivariable Cox proportional hazards models estimated hazard ratios and 95% confidence intervals for the associations between oral contraceptive use and breast cancer risk overall and by estrogen and progesterone receptor and human epidermal growth factor receptor 2 status. Oral contraceptive use was evaluated by status of use (current, former, and never), duration of and time since last use independently and cross-classified, and formulation (ie, estrogen and progestin type). Current oral contraceptive use was associated with a higher risk for invasive breast cancer (hazard ratio, 1.31; 95% confidence interval, 1.09-1.58) when compared with never use, with stronger associations observed for longer durations of current use (>5 years: hazard ratio, 1.56; 95% confidence interval, 1.23-1.99; ≤5 years: hazard ratio, 1.19; 95% confidence interval, 0.95-1.49). Among former users with >5 years since cessation, the risk was similar to that of never users (eg, >5 to 10 years since cessation: hazard ratio, 0.99; 95% confidence interval, 0.88-1.11). Associations did not differ significantly by tumor subtype. In analyses by formulation, current use of formulations containing levonorgestrel in triphasic (hazard ratio, 2.83; 95% confidence interval, 1.98-4.03) and extended cycle regimens (hazard ratio, 3.49; 95% confidence interval, 1.28-9.53) and norgestrel in monophasic regimens (hazard ratio, 1.91; 95% confidence interval, 1.19-3.06), all combined with ethinyl estradiol, was associated with a higher breast cancer risk when compared with never oral contraceptive use. No association was observed for current use of the other progestin types evaluated (norethindrone, norethindrone acetate, ethynodiol diacetate, desogestrel, norgestimate, and drospirenone), however, sample sizes were relatively small for some of the subgroups, limiting these analyses. Current oral contraceptive use was associated with a higher risk for invasive breast cancer regardless of disease subtype, however, the risk in former users was comparable with never users 5 years after cessation. In analyses by progestin type, associations were observed for select formulations containing levonorgestrel and norgestrel. Assessment of the associations for newer progestin types (desogestrel, norgestimate, drospirenone) was limited by sample size, and further research on more recently introduced progestins is warranted.

Little evidence for sex or ovarian hormone influences on affective variability

Women were historically excluded from research participation partly due to the assumption that ovarian hormone fluctuations lead to variation, especially in emotion, that could not be experimentally controlled. Although challenged in principle and practice, relevant empirical data are limited by single measurement occasions. The current paper fills this knowledge gap using data from a 75-day intensive longitudinal study. Three indices of daily affective variability—volatility, emotional inertia, and cyclicity—were evaluated using Bayesian inferential methods in 142 men, naturally cycling women, and women using three different oral contraceptive formulations (that “stabilize” hormone fluctuations). Results provided more evidence for similarities between men and women—and between naturally cycling women and oral contraceptive users—than for differences. Even if differences exist, effects are likely small. Thus, there is little indication that ovarian hormones influence affective variability in women to a greater extent than the biopsychosocial factors that influence daily emotion in men.

Natural and synthetic estrogens specifically alter nicotine demand and cue-induced nicotine seeking in female rats

Women have more difficulty maintaining smoking cessation than men, and experience greater withdrawal symptomatology as well as higher prevalence of relapse. Further, currently available treatments for smoking cessation, such as the nicotine patch and varenicline, have been shown to be less effective in women. Fluctuations in ovarian hormones across the menstrual cycle can affect craving and smoking relapse propensity. In addition, many women who smoke use some form of oral contraceptives, which most often contain ethinyl estradiol (EE), a synthetic, orally bio-available estrogen that is currently prescribed to women chronically and has been shown to alter smoking reward in women. The current study examined the impact of 17β-estradiol (E2), the prominent endogenous form of the steroid hormone estrogen, as well as EE, on nicotine self-administration, demand, and reinstatement following ovariectomy (OVX) or sham surgery. OVX vehicle-treated female rats consumed less nicotine, had lower intensity of demand, and reinstated less compared to sham vehicle-treated female rats. OVX-E2 and OVX-EE treatment groups showed a rebound of nicotine intake later in training, and Q0 levels of consumption were partially rescued in both groups. Further, E2 but not EE reversed the abolishment of reinstated nicotine seeking induced by OVX. Taken together, these results demonstrate that natural and synthetic estrogens play a critical role in mediating the neurobehavioral effects of nicotine, and future studies are essential for our understanding of how synthetic hormones contained within oral contraceptives interact with smoking.

Iron-Containing Oral Contraceptives and Their Effect on Hemoglobin and Biomarkers of Iron Status: A Narrative Review.

Oral contraceptive use has been associated with decreased menstrual blood losses; thus, can independently reduce the risk of anemia and iron deficiency in women. Manufacturers have recently started to include supplemental iron in the non-hormonal placebo tablets of some contraceptives. The aims of this narrative review are: (i) to describe the relationship between oral contraceptive use and both anemia and iron status in women; (ii) to describe the current formulations of iron-containing oral contraceptives (ICOC) available on the market; and (iii) to systematically review the existing literature on the effect of ICOC on biomarkers of anemia and iron status in women. We discovered 21 brands of ICOC, most commonly including 25 mg elemental iron as ferrous fumarate, for seven days, per monthly tablet package. Our search identified one randomized trial evaluating the effectiveness of ICOC use compared to two non-ICOC on increasing hemoglobin (Hb) and iron status biomarker concentrations in women; whereafter 12 months of contraception use, there were no significant differences in Hb concentration nor markers of iron status between the groups. ICOC has the potential to be a cost-effective solution to address both family planning needs and iron deficiency anemia. Yet, more rigorous trials evaluating the effectiveness of ICOC on improving markers of anemia and iron deficiency, as well as investigating the safety of its consumption among iron-replete populations, are warranted.

Oral contraceptive use is not related to gender self-concept

Oral contraceptive (OC) use is a valuable and underutilized natural experiment for examining exogenous hormone effects on aspects of cognition and behavior, especially aspects that show sex or gender differences. OC use, however, is not randomly assigned; women who use OCs may systematically differ from non-users for gender-linked reasons that potentially confound investigations of the pharmacokinetic effects of OCs. Thus, the primary aim of this study was to investigate whether OC users and non-users differ in gender self-concepts, as sociocultural factors might influence who uses OCs and why. A secondary aim was to examine whether OC users of different pill formulations differ in gender self-concept. Multivariate analyses of covariance (controlling for age) on a large sample of 395 young adult women revealed no significant differences between OC users (n = 247) and non-users (n = 148) in four aspects of gender self-concept (expressivity, instrumentality, femininity, and masculinity), with univariate effect sizes averaging d = 0.07. Moreover, inferences about group differences did not change when considering sociocultural factors (i.e., reason for OC use) or pharmacokinetic properties of the pills (i.e., androgenicity). Thus, findings indicate that differences in gender self-concept do not underlie OC use and non-use, and that the androgenicity of different OC formulations does not impact gender self-concept. Taken together, findings also highlight the specificity of exogenous ovarian hormone influences, as there are documented effects on cognition but not on personal characteristics, such as gender self-concept.

Effect of oral contraceptives on total and bioavailable 25-hydroxyvitamin D

Studies show an increase in circulating levels of 25-hydroxyvitamin D [25(OH)D] in women using combined oral contraceptives (COCs). 25(OH)D is a quantitatively important metabolite and widely used clinical marker of vitamin D status and is regulated by vitamin D binding protein (VDBP). However, studies have not identified the type of formulations used by the women, and there are no data on the effect of progestins on 25(OH)D levels. Our study objective was to compare the effects of two COC formulations [ethinyl estradiol (EE)/norethindrone acetate (NETA) vs. EE/levonorgestrel (LNG)] as well as LNG alone on total and bioavailable (free plus albumin-bound) 25(OH)D levels in serum samples collected at baseline, mid treatment, and end of treatment. Total 25(OH)D and VDBP were measured by immunoassay, and bioavailable 25(OH)D was calculated. The results show that with the EE/NETA formulation, total and bioavailable 25(OH)D and VDBP levels increased non-significantly by 7.4 %, 14.9 %, and 10 %, respectively, from baseline to end of treatment. In contrast, the corresponding changes with EE/LNG showed an increase of 4.4 % in total 25(OH)D but a significant decrease of 18.2 % in bioavailable 25(OH)D and increase of 19.1 % in VDBP. When LNG was administered alone, no significant changes were observed in total and bioavailable 25(OH)D or VDBP levels during the course of treatment. Our findings show considerably different effects on total and bioavailable 25(OH)D levels, as well as VDBP levels, with different oral contraceptive formulations. LNG may have a suppressive effect on VDBP, similar to its well-known androgenic effect on SHBG. Further studies are needed to determine the effect of hormonal contraceptive formulations on vitamin D status and its potential impact on women’s health.

Approaches Used to Improve Adherence to Oral Contraceptives

Objectives: The objective of this review the approaches for improving oral contraceptives (OCs) adherence.Methods: The search strategy involved the use of the following data bases: Cochrane Library, Pubmed,hinari, a Pop Line, Scopus, Science direct, the Cochrane register of Controlled Trials. Types of study areoriginal Research studies, RCTs, systematic reviews, full text articles.Results: Adherence is a shared responsibility of patients, clinicians, and manufacturers; the patient andclinician are the focal points for these efforts. Counseling must be individualized, which requires knowledgeof factors that predict adherence and understanding of the patient’s decision making process as it relates tomedications.Conclusion: Improving adherence and preventing early discontinuations is a shared responsibility of OCsusers, health care providers, and OCs manufacturers. Manufacturers should recognize that the provisionof written materials that are both informative and easy to understand can improve patient compliance.Continued improvements in OCs formulations are important in reducing unwanted side effects. However,our findings suggest that providers are the focal point for helping women to become more successful OCsusers.

Oral contraceptive use by formulation and endometrial cancer risk among women born in 1947\u20131964: The Nurses\u2019 Health Study II, a prospective cohort study

Oral contraceptives (OCs) have been associated with long-term lower endometrial cancer risk; relatively little is known about associations with more recent OC formulations and associations with longer-term risk. A total of 107,069 women from the Nurses’ Health Study II recalled OC use from age 13 to baseline (1989); biennial questionnaires updated data on OC use until 2009. OCs were classified by estrogen and progestin type, dose, and potency based on reported brand. 864 incident endometrial cancer cases were identified through 2017. Multivariable Cox proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals [95% CI] for the association of OC use with endometrial cancer risk. OC use was associated with lower endometrial cancer risk (ever use, HR 0.77 [95% CI 0.65–0.91]; >10 years of use, 0.43 [0.32–0.58] vs. never OC use). Inverse associations for duration were evident regardless of time since last use. Longer durations (> 5 years) of ethinyl estradiol (0.52 [0.41–0.67]) and second-generation progestins (0.43 [0.30–0.61]), both versus never use, were more strongly associated with lower risk than mestranol (0.66 [0.50–0.88], p-het = 0.01) and first-generation progestins (0.62 [0.49–0.78], p-het = 0.03). Inverse associations were generally observed for cross-classified cumulative average estrogen and progestin dose and potency (< vs. ≥ median; ever use vs. never OC use), with the exception of high estrogen and low progestin dose. OCs were associated with lower endometrial cancer risk, independent of time since last use. Use of ethinyl estradiol and second-generation progestins were more strongly inversely associated with risk compared with older formulations.

Genotoxic effects of drospirenone and ethinylestradiol in human breast cells (in vitro) and bone marrow cells of female mice (in vivo)

Estrogen and progesterone congeners as found in various oral contraceptive formulations have been implicated as the cause of cancer in sex and tissue-specific targets. The mechanism of carcinogenesis by sex steroids is still debatable. In this study, we evaluated the genotoxicity induced by two components of one of the commonly used oral contraceptive formulation; drospirenone and ethinylestradiol in human breast cells (MCF-7) in vitro and in bone marrow cells of female mice in vivo. DNA damage was assessed by alkaline comet assay. Both of the drugs produced DNA damage in human breast cells at exposure concentrations which are about 100-fold and above than normally found in human blood after their lowest recommended doses. The DNA damage was produced only after metabolic activation by mice liver S-9 fraction in both cases. The co-exposure with both the compounds at median exposure levels resulted in potentiation of DNA damage. In bone marrow cells of adult female mice, both the compounds produced DNA damage at human equivalent doses after exposure was carried out repeatedly for approximately one estrus cycle (5 days). The co-administration with the compounds resulted in potentiation of DNA damage as indicated by percent tail DNA in comet assay. Thus it is concluded that drospirenone and ethinylestradiol cause DNA damage in certain target specific tissue (mammary epithelial cells) and in female bone marrow cells. The co-exposure with drospirenone and ethinylestradiol results in potentiation of genotoxicity which may pose a threat of cancer development in women taking these drugs for long periods.

Ethinyl estradiol vs estradiol valerate in combined oral contraceptives – Effect on glucose tolerance: A randomized, controlled clinical trial

ObjectiveTo compare the effects of two formulations of combined oral contraceptives (COCs), estradiol valerate (EV) and ethinyl estradiol (EE) combined with dienogest (DNG), and DNG-only, on glucose tolerance. Study DesignWe performed a randomized, controlled 9-week clinical trial. Inclusion criteria were: age 18–35 years, regular menstrual cycle (28 ± 7 days), no polycystic ovaries, non-smoking, no contraindications for COC use and a 2-month wash-out from hormonal contraceptive use. The women were randomized to EV + DNG (n = 20), EE + DNG (n = 20), and DNG-only (n = 19), and evaluated at baseline, at 4–5 weeks and 8–9 weeks of treatment. Study medications were used continuously for 63 days. Primary outcome measure was change in the whole-body insulin sensitivity index (Matsuda index) derived from the oral glucose tolerance test (OGTT) over the treatment period. Secondary outcome measures were area under curves (AUC) of glucose and insulin, homeostatic model assessment – insulin resistance (HOMA-IR) and Insulin Sensitivity Index (ISI). ResultsFifty-nine women enrolled, and 56 women completed the study. The Matsuda index changed from baseline as follows (mean percentage change, mean change [95%CI]): DNG-only −12%, −1.45 [95%CI −3.22–0.325] P = 0.10; EV + DNG + 2.7%, −0.10 [−1.34 to 1.14] P = 0.86; EE + DNG −5.5%, −1.02 [−2.51 to 0.46] P = 0.16, comparing the groups P = 0.27. There were no clinically significant differences in glucose tolerance between the COC groups, but the DNG-only group showed an improvement in the 2-h glucose levels (5.5 [95%CI 5.0–6.0] to 4.7 mmol/l [4.2–5.2], P = 0.001). ConclusionWe found no clinically significant differences between EV and EE combined with DNG and DNG-only on glucose tolerance in healthy, young, normal-weight women, indicating that these preparations appear close to neutral regarding glucose metabolism when used continuously for nine weeks. ImplicationsCombinations of both ethinyl estradiol and natural estradiol (estradiol valerate) with dienogest (DNG), as well as DNG-only, seem metabolically safe in young and healthy women in short-term continuous use.

Risk of sexual dysfunction with progestin-based contraceptives in women of child-bearing age.

To examine whether there is a positive association between sexual dysfunction (SD) and different types of progestin-based contraceptives. Nested case-control study in women of child-bearing age (15-45 years) from the IQVIA® Ambulatory electronic medical record database from 2008 to 2018. Cases defined by diagnosis of sexual dysfunction identified by international classification for disease clinical modification code 9th and 10th. Each case was matched to four controls and rates of prescriptions of the following were compared: levonorgestrel intra-uterine device (IUD), progestin, and ethinyl estradiol (EE) combined oral contraceptive (COC) formulations including levonorgestrel, norgestimate, drospirenone, desogestrel, norethindrone, and norgestrel; etonogestrel vaginal ring; and medroxyprogesterone injection. Overall, 6689 cases of patients with SD were matched to 26,756 matched controls. Compared with matched controls, more subjects with SD used levonorgestrel IUD (OR 1.24, 95% CI 1.08-1.44), EE-levonorgestrel COC (OR 1.18, 95% CI 1.00-1.41), EE-drospirenone (OR 1.28, 95% CI 1.00-1.67), and medroxyprogesterone (OR 1.38, 95% CI 1.12-1.70). The use of norgestrel exhibited a protective effect (OR 0.83, 95% CI 0.73-0.95). When using the EE-levonorgestrel COC as a comparator, norgestrel users exhibited a protective effect (OR 0.70, 95% CI 0.57-0.87) while no other contraceptives showed a statistically significant difference in association with SD. Our study found an increase in the use of levonorgestrel (COC and IUD), drospirenone, and medroxyprogesterone in subjects with SD. The risk of contraceptives did not differ when compared with oral levonorgestrel. The small association size and lack of difference between drug formulations suggest a minimal impact of progestin-based contraceptives on sexual dysfunction.

Effects of Oral Contraceptive Androgenicity on Visuospatial and Social-Emotional Cognition: A Prospective Observational Trial.

Oral contraceptives (OCs) containing estrogen and progesterone analogues are widely used amongst reproductive-aged women, but their neurocognitive impact is poorly understood. Preliminary studies suggest that OCs improve verbal memory and that OCs with greater androgenic activity may improve visuospatial ability. We sought to explore the cognitive impact of OCs by assessing performance of OC users at different stages of the OC cycle, and comparing this performance between users of different OC formulations according to known androgenic activity. We conducted a prospective, observational trial of OC users, evaluating cognitive performance with CogState software on two occasions: days 7–10 of active hormonal pill phase, and days 3–5 of the inactive pill phase (coinciding with the withdrawal bleed resembling menstruation). Thirty-five OC users (18 taking androgenic formulations, 17 taking anti-androgenic) were assessed. Analysis by androgenic activity showed superior performance by users of androgenic OCs, as compared to anti-androgenic OCs, in visuospatial ability and facial affect discrimination tasks. A growing understanding of cognitive effects of OC progestin androgenicity may have implications in choice of OC formulation for individuals and in future OC development.

Evaluation of different antiandrogenic progestins on clinical and biochemical variables in polycystic ovary syndrome

Objectives: The aim of the study was to update the results of a previous study published 10 years ago and compare the effect on hyperandrogenism of a newer progestin, dienogest (DNG), in a combined oral contraceptive (COC) formulation with ethinylestradiol (EE), with that of COCs containing the same dose of EE in combination with drospirenone (DRSP) and chlormadinone acetate (CMA).Methods: Sixty women with polycystic ovary syndrome (PCOS) aged between 16 and 35 and requiring antiandrogenic contraceptive treatment were randomised to one of three treatment groups: EE 30 µg/DRSP 3 mg, EE 30 µg/CMA 2 mg, EE 30 µg/DNG 2 mg. We evaluated the effects of the three COCs on sex hormone-binding globulin (SHBG) and biochemical markers of hyperandrogenism.Results: After 3 months of treatment, serum androgen concentrations were significantly improved in all treatment groups. Serum concentrations of SHBG were significantly increased with all COC treatments (p < 0.0001). Interestingly, DRSP had a greater effect (+218%; p < 0.0001) on serum SHBG concentrations compared with DNG and CMA (p < 0.04 and p < 0.002, respectively). Serum concentrations of total testosterone significantly decreased in all groups (p < 0.0001). DRSP had a significantly greater effect on total testosterone concentrations compared with DNG (p = 0.002) and CMA (p < 0.0001).Conclusion: Our study showed that DNG exerted an important stimulatory effect on SHBG concentrations, which was less than that of DRSP but greater than that of CMA. Similar results were also obtained for dehydroepiandrosterone sulphate and total testosterone.

Associated Risk Between Use of Oral Contraceptive Pills and Three Types of Breast Cancer: ER+, ER-, and TN

Around 9.5 million women between the ages of 15 and 44 use some form of oral contraceptives. Oral contraceptive pills typically consist of progestin and estrogens, synthetic versions of the hormones that a female-bodied person naturally produces and are used by many people for a various number of reasons; such reasons include regulating acne, controlling hormone production, and preventing pregnancy. One in eight women in the US is diagnosed with breast cancer over the course of her lifetime, and many of these cancers have hormone-related causes. However, there are three types of breast cancer specifically linked to the hormones that are found in oral contraceptive pills: estrogen receptor-positive, estrogen receptor-negative, and triple-negative. While the potential of oral contraceptive-related causes for these breast cancers have been studied at great length, researchers are often unable to confirm their finding of an associated risk between synthetic hormones in oral contraceptives and certain types of breast cancer. Many studies agree that this associated risk exists, but stress the need for more involved research with more detailed and specific objectives. This literature review will provide insight into limitations of current research on the associated risk between oral contraceptives and breast cancer in order to fill research gaps and evaluate the certainty of current findings.

The Effect of Oral Contraceptive Hormones on Anterior Cruciate Ligament Strength

Background: Women are 2 to 9 times more likely to experience an anterior cruciate ligament (ACL) injury than men. Various hormones including relaxin, progesterone, and estrogen influence ACL strength. Oral contraceptives (OCs) alter these hormone levels; however, studies have yet to comprehensively compare different OCs’ effects on the ACL. Hypothesis: OCs with increased progestin-to-estrogen ratios will (1) increase ACL collagen expression, (2) decrease ACL matrix metalloproteinase expression, and (3) increase ACL strength. Study Design: Controlled laboratory study. Methods: Untreated female rats were compared with rats treated with 1 of 5 clinically used OCs: norethindrone (NE) only, NE plus ethinylestradiol (EE), etynodiol diacetate (ED) plus EE, norgestimate (NG) plus EE, and drospirenone (DS) plus EE. Doses were scaled from human doses to account for differences in bioavailability and body weight, and OCs were administered daily via oral gavage for 4 rat estrous cycles (20 days). A total of 36 rats were then sacrificed (6 rats/group). ACLs underwent biomechanical testing to assess ACL strength, stiffness, and maximum load before failure. ACL specimens were also isolated for quantitative real-time polymerase chain reaction analysis to assess collagen, matrix metalloproteinase, and relaxin receptor–1 expression. Results: While the primary structural property of interest (ACL maximum load before failure) was not significantly improved by OC treatment, the main material property of interest (ACL strength) in rats treated with NE only, DS + EE, ED + EE, and NE + EE was significantly increased compared with untreated controls (P = .001, P = .004, P = .004, and P = .04, respectively). The order from strongest to weakest ACLs, which was also the same order as the highest to lowest progestin-to-estrogen ratios, was groups treated with NE only, DS + EE, ED + EE, NE + EE, and lastly NG + EE. Higher ratio formulations also increased the expression of type I collagen (P = .02) and decreased the expression of matrix metalloproteinase–1 (P = .04). Conclusion: OC formulations with higher progestin-to-estrogen ratios may be more protective for the ACL than formulations with lower ratios. Clinical Relevance: OC formulations with high progestin-to-estrogen ratios may benefit female athletes by reducing their ACL injury risk by decreasing the effects of relaxin on the ACL.

Hormone replacement therapies, oral contraceptives, reproductive factors and colorectal adenoma risk: a systematic review and dose-response meta-analysis of observational studies.

The association between the use of oral contraceptives and hormone replacement therapy (HRT) or other reproductive factors and the risk of colorectal adenoma (CRA) remains controversial. Our study aimed to review the evidence by conducting a dose-response meta-analysis to investigate this association. We searched PubMed and Embase databases for relevant studies published until May 2017. Traditional and dose-response meta-analyses were conducted. Sensitivity analysis was performed to evaluate the robustness of the results. Cumulative meta-analysis was used to assess the risk of different oral contraceptive formulations or generations. A total of 19 observational studies, with 21923 CRA cases and 1030711 participants, were included in the meta-analysis. Ever HRT use showed a potential inverse association with CRA risk [relative risk (RR) 0.83, 95% CI 0.70-1.00]. The dose-response meta-analysis further demonstrated that HRT use could reduce CRA risk. Compared with no HRT use, the predicted RRs were 0.82 (95% CI 0.67-0.99), 0.76 (95% CI 0.59-0.98) and 0.77 (95% CI 0.62-0.96) for 3, 6 and 9years of HRT use, respectively. All other factors were not statistically significantly associated with CRA risk. This study indicated that only HRT use might reduce the risk of developing CRA. Any advice regarding HRT use to prevent CRA should be tailored to the individual risks and potential benefits. Large, well-designed prospective studies with long-term follow-up are required to further clarify the aetiology of CRA.