Oral Combined Hormonal Contraceptives Research Articles

Development of a Translational Exposure-Bracketing Approach to Streamline the Development of Hormonal Contraceptive Drug Products.

Worldwide, 922 million women of reproductive age (or their partners) use some sort of contraception to prevent pregnancy. Oral combined hormonal contraceptives (CHCs) typically utilize a combination of a progestin and an estrogen. CHCs are potentially at risk to metabolic drug-drug interaction (DDI) via CYP3A4, the main enzyme involved in the oxidative metabolism of ethinyl estradiol and most progestins (e.g., levonorgestrel (LNG) and drospirenone (DRSP)). Recently, the US Food and Drug Administration (FDA) issued a guidance addressing metabolic DDIs in the realm of CHC, establishing an overall class-based recommendation with respect to avoidance of CYP3A4 induction interactions. Given that different progestins have varying magnitudes of fraction metabolized by CYP3A4 (fmCYP3A4 ), it would be of clinical benefit to determine if all progestins are at the same risk to CYP3A4-mediated metabolic DDIs. LNG and DRSP are commonly used progestins that are at the margins of the rifampicin induction effect observed in vivo because they have the relatively lowest and highest fmCYP3A4 among commonly used CHC formulations containing norgestimate, desogestrel, norgestrel, and norethindrone. Therefore, we applied a multi-pronged strategy (i.e., (i) development of the physiologically-based pharmacokinetic models; (ii) comparison of the effect of CYP3A inducers and inhibitors on DRSP vs. LNG; and (iii) providing the clinical-practice context based on real-world data, to explore the difference in DDI risk for oral CHCs.

Risk of venous thromboembolism during the use of oral estrogen-progestogen hormone therapies in light of most recent research findings.

Two important studies evaluating the safety profile of oral estrogen-progestogen hormonal therapies conducted in standard clinical practice with respect to the venous system were recently published.A large prospective controlled cohort study (PRO-E2) based on the non-inferiority design has shown that the relative risk of developing venous thrombosis (VTE) in women using combined oral hormonal contraceptives (COHC) containing 17β-estradiol (1.5 mg) and nomegestrol acetate (2.5 mg) (E2/NOMAC) was not statistically different from that in users of COHC containing ethinylestradiol and levonorgestrel (EE/LNG).The aim of the recently presented study was to compare the risk of VTE in patients treated with a product for oral continuous combined menopausal hormone therapy containing 1 mg of 17ß-estradiol and 100 mg of micronized progesterone (1 mgE2/100 mgP4) with patients taking conjugated equine estrogens and medroxyprogesterone acetate (CEE/MPA). The study was based on an analysis of records retrieved from a US health insurance database, and was therefore concerned the real-life clinical practice. The hazard ratio of VTE when comparing 1 mgE2/100 mgP4 with CEE/MPA was 0.70 (95% CI: 0.53–0.92). The difference was found to be statistically significant (p < 0.05).The rewieved studies provide further evidence that the use of hormones bioidentical with endogenous steroids in oral contraception and menopausal hormone therapy creates an opportunity to combine high efficacy with a favorable safety profile.

There is no association between combined oral hormonal contraceptives and depression: a Swedish register-based cohort study.

To investigate whether users of hormonal contraceptives (HCs) are at increased risk of depression compared with non-users. Register-based cohort study. Sweden. Women aged 15-25 years between 2010 and 2017 with no prior antidepressant treatment, psychiatric diagnose or contraindication for HCs (n = 739 585). Women with a prescription of HC were identified via the Swedish Prescribed Drug Register (SPDR). Relative risks (RRs) for first depression diagnosis in current HC-users compared with non-users were modelled by Poisson regression. Adjustments included age, medical indication for HC-use and parental history of mental disorders, among others. Depression, captured by a redeemed prescription of antidepressant treatment, or a first depression diagnosis in the SPDR and the National Patient Register. Compared with non-users, women on combined oral contraceptives (COCs) and oral progestogen-only products had lower or no increased risk of depression, relative risk (RR) 0.89 (95% CI 0.87-0.91) and 1.03 (95% CI 0.99-1.06) after adjustments, respectively. Age-stratified analyses demonstrated that COC use in adolescents conferred no increase in risk (RR 0.96, 95% CI 0.93-0.98), whereas use of progestogen-only pills (RR 1.13, 95% CI 1.07-1.19), contraceptive patch/vaginal ring (RR 1.43, 95% CI 1.30-1.58), implant (RR 1.38, 95% CI 1.30-1.45) or a levonorgestrel intrauterine device (RR 1.59, 95% CI 1.46-1.73) were associated with increased risks. This study did not find any association between use of COCs, which is the dominating HC in first time users, and depression. Non-oral products were associated with increased risks. Residual confounding must be addressed in the interpretation of the results. There is no association between combined hormonal contraceptives and depression.

Combined hormonal contraceptives are associated with minor changes in composition and diversity in gut microbiota of healthy women

Recent human and animal studies have found associations between gut microbiota composition and serum levels of sex hormones, indicating that they could be an important factor in shaping the microbiota. However, little is known about the effect of regular hormonal fluctuations over the menstrual cycle or CHC-related changes of hormone levels on gut microbiota structure, diversity and dynamics. The aim of this study was to investigate the effect of CHCs on human gut microbiota composition. The effect of CHC pill intake on gut microbiota composition was studied in a group of 7 healthy pre-menopausal women using the CHC pill, compared to the control group of 9 age-matched healthy women that have not used hormonal contraceptives in the six months prior the start of the study. By analyzing the gut microbiota composition in both groups during one menstrual cycle, we found that CHC usage is associated with a minor decrease in gut microbiota diversity and differences in the abundance of several bacterial taxa. These results call for further investigation of the mechanisms underlying hormonal and hormonal contraceptive-related changes of the gut microbiota and the potential implications of these changes for women's health. This article is protected by copyright. All rights reserved.

Weekly evaluation of estrogen α and progesterone receptors in the mammary epithelium of women after the use of combined oral hormonal contraceptives for one month

The increased risk of breast cancer (BC) is the most controversial adverse effect of combined oral hormonal contraceptives (COHC). An evaluation of hormone receptors (HR) revealed that their expressions are inversely proportional to the rate of cell proliferation, with a hierarchy where proliferative cells would be controlled by paracrine factors released by positive HR cells. Thus, the greater the proliferation, the greater the risk of the actions of environmental carcinogens. Compare the expressions by immunohistochemistry (IHC) of estrogen α (ERα) and progesterone receptors (PR) weekly in the mammary epithelium (ME) of patients using COHC for one month with those in the natural cycle. Retrospective cohort study of 118 women, 42 of whom were excluded and with a final sample of 76 women. Study group (A) consisted of 31 users of COHC with 30 µg of ethinyl estradiol (EE) and 150 µg of levonorgestrel (L), and control group (B), 45 non-users of COHC. In parity comparison, the Fisher's exact test was used, and for the mean ages, the Student’s t-test for independent samples. The Generalized Estimation Equation (EEG) model was used to evaluate ERα and PR counts over the four weeks and compare them. The Analysis of Variance (ANOVA) with two fixed factors and the Kolmogorov-Smirnov test were used to compare the total ERα and PR counts. Statistical analyses were performed using the SPSS 20.0 and STATA 12 programs, with a significance level of 5% (p≤0.05). As for age, group B had a mean age of 23.7±5.9 years compared to group A, with a mean age of 20.5±5.1 years, statistically significant p=0.016. With regard to parity, group A presented 83.9% of nulligravida versus 73.3% in group B, with p=0.164 without statistical significance. According to GEE, group A had higher mean percentages of ERα (p&lt;0.001) and PR (p&lt;0.001) when compared to women in the control group. The expressions of the IHC of the ERα and PR in percentages, weekly in the ME of the patients in the users of COHC presented higher mean percentages of ERα and PR, both statistically significant, when compared with non-users.

One‐year adolescent bone mineral density and bone formation marker changes through the use or lack of use of combined hormonal contraceptives

ObjectiveThe objective of this study was to evaluate the effects of two low‐dose combined oral contraceptives on bone metabolism in adolescents for one year. MethodsThis was a quasi‐experimental study. The adolescents were divided into three groups: oral contraceptives 1 (n=42) (20μg EE/150μg desogestrel), oral contraceptives 2 (n=66) (30μg EE/3mg drospirenone), and a control group (n=70). Adolescents underwent anthropometric assessment and densitometry (dual‐energy X‐ray). Bone age and bone formation markers (osteocalcin and bone alkaline phosphatase) were evaluated. The oral contraceptives users were evaluated again after 12 months. Linear regression analysis was used to indirectly study the effect of each additional year of chronological age on anthropometric and densitometric variables as well as on bone markers in the control group. ResultsAt study entry, no significant differences were observed between the oral contraceptives 1, oral contraceptives 2, and controls in the analyzed variables. Linear regression analysis showed an increase in bone mineral density and bone mineral content for each additional year. There was a significant reduction in bone alkaline phosphatase levels; no significant difference was observed for osteocalcin in control individuals. Comparison of dual‐energy X‐ray variables at baseline and after one year showed no significant differences in the oral contraceptives 1 or oral contraceptives 2 groups. A significant reduction in bone alkaline phosphatase and osteocalcin levels was observed in both the oral contraceptives 1 and oral contraceptives 2 groups. ConclusionAdolescent women gain peak bone mass during this phase of life. Two low‐dose combined oral hormonal contraceptives were associated with lower bone gain and lower bone formation markers than in untreated controls.

Searching for Information on the Risks of Combined Hormonal Contraceptives on the Internet: A Qualitative Study Across Six European Countries.

BackgroundSearching for health information online is increasingly common and is an obvious source of information about oral combined hormonal contraceptives (CHCs) and their risks. However, little is known about how publicly available websites address the risks of CHCs, particularly venous thromboembolism (VTE).ObjectiveThe aim was to explore the information available to women about VTE and other risks of CHCs on websites available through commonly used search engines.MethodsA qualitative study was conducted to explore whether and how websites about CHCs in Denmark, Germany, Netherlands, Slovakia, Spain, and the United Kingdom make reference to VTE and other CHC risks. A systematic search procedure was adopted across the six countries, based on relevant keywords. The search was carried out using the Google search engine by fluent/native speakers of each language. A content analysis approach was conducted to extract information from the selected websites.ResultsA total of 357 websites were reviewed. Nearly all (343/357, 96.1%) the websites mentioned VTE as a risk of CHCs, with approximately half referring to other side effects as well. One-fifth (92/357, 25.8%) of the websites provided suggestions about the best contraceptive method to use, and only a minority (23/357, 6.4%) recommended women discuss CHCs with their health professionals. Sites were generally run by the media (110/357 30.8%) or medical services from nongovernmental organizations (140/357, 39.2%). Only a minority of websites referred to organizations such as the European Medicines Agency (11/357, 3.1%).ConclusionsDespite the large number of websites containing information about oral CHCs and their risks, particularly VTE, only a limited number referred to information from accredited health agency sources. We argue this is a missed opportunity for accredited health agencies to share high-quality information to assist women using CHCs to make informed decisions about contraception.

Contraception Update: Extended Use of Long Acting Methods, Hormonal Contraception Risks, and Over the Counter Access.

The clinical update serves as a brief review of recently published, high-impact, and potentially practice changing journal articles summarized for our readers. Topics include menopause, sexual dysfunction, breast health, contraception, osteoporosis, and cardiovascular disease. For this clinical update, we reviewed both reproductive and general medical journals for clinically relevant publications related to the use of contraceptive methods. We have chosen to highlight articles examining the extended use of highly effective (long-acting) methods, complications of implants, risks associated with oral combined hormonal contraceptives, and the availability of over the counter contraception.

Cross-sectional evaluation of the impact of information on flexible extended regimens of oral contraceptives in the choices made by women seeking contraceptive counselling: the FLEXO study

Objective: Oral combined hormonal contraceptives (CHCs) are available that limit the number of menses when used in a flexible extended regimen. Our aim was to investigate the decision-making processes of women presented with a flexible extended CHC option.Methods: The FLEXO study is an epidemiological, cross-sectional, multicentre study conducted under typical clinical practice conditions to determine women’s acceptance of a flexible continuous CHC regimen versus a cyclical 21/7 day regimen, after receiving standardised information during contraceptive counselling.Results: A total of 1350 women were invited to participate, of whom 1156 were enrolled. Of these, 47.2% chose the flexible extended CHC regimen. Their main reason for choosing this regimen was to reduce the number of menses (25.7%), followed by the desire to avoid symptoms related to menstruation (21.6%). The reasons given for rejecting this regimen were the desire to have monthly menstrual cycles (24.9%) and the fear of becoming pregnant and not being aware of it due to the absence of menstruation (18.1%).Conclusion: Many women chose the extended flexible regimen when they received information about this option. Women primarily chose this pattern to relieve or eliminate discomfort related to menstruation.

One-year adolescent bone mineral density and bone formation marker changes through the use or lack of use of combined hormonal contraceptives

ObjectiveThe objective of this study was to evaluate the effects of two low-dose combined oral contraceptives on bone metabolism in adolescents for one year. MethodsThis was a quasi-experimental study. The adolescents were divided into three groups: oral contraceptives 1 (n=42) (20μg EE/150μg desogestrel), oral contraceptives 2 (n=66) (30μg EE/3mg drospirenone), and a control group (n=70). Adolescents underwent anthropometric assessment and densitometry (dual-energy X-ray). Bone age and bone formation markers (osteocalcin and bone alkaline phosphatase) were evaluated. The oral contraceptives users were evaluated again after 12 months. Linear regression analysis was used to indirectly study the effect of each additional year of chronological age on anthropometric and densitometric variables as well as on bone markers in the control group. ResultsAt study entry, no significant differences were observed between the oral contraceptives 1, oral contraceptives 2, and controls in the analyzed variables. Linear regression analysis showed an increase in bone mineral density and bone mineral content for each additional year. There was a significant reduction in bone alkaline phosphatase levels; no significant difference was observed for osteocalcin in control individuals. Comparison of dual-energy X-ray variables at baseline and after one year showed no significant differences in the oral contraceptives 1 or oral contraceptives 2 groups. A significant reduction in bone alkaline phosphatase and osteocalcin levels was observed in both the oral contraceptives 1 and oral contraceptives 2 groups. ConclusionAdolescent women gain peak bone mass during this phase of life. Two low-dose combined oral hormonal contraceptives were associated with lower bone gain and lower bone formation markers than in untreated controls.

Immune profile in relation to sex steroid cyclicity in healthy women and women with multiple sclerosis

To prospectively study systemic in vivo immunological effects of sex hormones, using different phases of oral combined hormonal contraceptives (CHC), and the natural menstrual cycles in both healthy women and in women with multiple sclerosis (MS), blood samples from sixty female MS patients and healthy controls with and without CHC were drawn in high and low estrogenic/progestogenic phases. Expression of Th-associated genes in blood cells was determined by qPCR and a panel of cytokines and chemokines was measured in plasma. High hormone level phases were associated with increases in Th1 (TBX21) and Th2 (GATA3) associated markers, as well as the B cell-associated chemokine CXCL13, while the inhibitory regulator CTLA-4 was decreased. These changes were not observed in MS patients, of whom most were treated with immunomodulatory drugs. Our data indicate immune activating properties in vivo of high steroid sex hormone levels during both CHC and normal menstrual cyclicity.

Efficacy and side-effects profile of the ethinylestradiol and etonogestrel contraceptive vaginal ring: a systematic review and meta-analysis

Objective: To assess the efficacy and tolerability (side-effects profile), and compliance of the combined contraceptive vaginal ring (CCVR) compared with combined oral hormonal contraceptives (COC). Data sources: The PubMed, Embase, POPLINE, Cochrane Central Register of Controlled Trials (CENTRAL), LILACS, ClinicalTrials.gov, Clinical Trials Registry Platform (ICTRP) and CINAHL databases were searched. Methods of study selection: Electronic databases were searched for randomised clinical trials comparing the CCVR with COC with a duration of at least 3 months between 01 December and 15 December 2015. The primary outcome was efficacy. The secondary outcomes were compliance, absence of withdrawal bleeding, breakthrough bleeding, nausea and headache. Heterogeneity was assessed using I 2 statistic and Cochran's Q statistic. Results were expressed as odds ratios (OR) with 95% confidence intervals (CIs) using random-effects models or fixed-effects models depending on the heterogeneity. Results: 4368 records were identified, 2844 of which were removed after duplicates and 1524 records were screened. Of these, 1503 were excluded and 21 full text articles were assessed for eligibility. After removing another 7 articles, 14 records were finally included in the qualitative and quantitative analysis. The results show a trend to higher efficacy for the CCVR in preventing pregnancy (Peto OR: 0.52 [95% CI: 0.26–1.04]) and a significantly lower presence of nausea (Peto OR: 0.66 [95% CI: 0.46–0.93]). More cycles were compliant in the CCVR group (Peto OR: 1.22 [95% CI: 1.12–1.32]) and fewer women reported breakthrough bleeding (Peto OR: 0.68 [95% CI: 0.51–0.91]). Conclusions: Our findings demonstrate that the CCVR is as effective and tolerable as the COC but with a better bleeding profile.

Lupus érythémateux systémique et contraception : revue systématique de la littérature

ObjectiveThe aim of our study was to evaluate the safety of contraceptive methods use among women with systemic lupus erythematosus (SLE). MethodsA systematic review of the literature was performed using the two databases MEDLINE and SCOPUS, in order to identify articles concerning the safety of contraceptive methods use among women with SLE, through May 2016. Information on study characteristics, objectives, population, contraception and outcomes were extracted. ResultsA total of 907 articles were identified and 21 were selected for the systematic review. Two randomised controlled trials found no worsening of disease activity with the use of combined oral contraceptive in women with stable or inactive SLE. Disease activity was not exacerbated with the use of progestogens-only contraceptive. There was an increased risk of thrombosis with the use of combined contraceptive, particularly in women with positive antiphospholipid antibodies and this must lead to a restriction of use in these patients. ConclusionUse of oral combined hormonal contraceptives should be limited to patients with non-severe and stable disease, without thrombosis risk factors.

Noncontraceptive use of oral combined hormonal contraceptives in polycystic ovary syndrome-risks versus benefits.

The use of steroid sex hormones for noncontraceptive benefits has been endorsed by several medical societies. In women with polycystic ovary syndrome (PCOS), hormonal contraceptives are first-line therapy for concurrent treatment of menstrual irregularity, acne, and hirsutism. The association of PCOS with obesity, diabetes, and dyslipidemia frequently brings up the debate regarding risks versus benefits of hormonal contraceptives in this population. In women with PCOS, the lack of large-scale studies evaluating the risks with varying doses of ethinyl estradiol, types of progestins, and presence of confounding factors such as obesity, smoking, and other cardiometabolic comorbidities is a significant limitation in these deliberations. Although it is important to assess the absolute risk for major morbidities including cardiovascular events, currently, there are a paucity of long-term data for these outcomes in PCOS. Most of the current studies do not suggest an increase in risk of prediabetes/diabetes, clinically significant dyslipidemia, inflammatory changes, or depressive/anxiety symptoms with oral contraceptive pill use. Screening of women with PCOS for cardiometabolic and psychiatric comorbidities is routinely recommended. This information should be used by health care providers to individualize the choice of hormonal contraceptive treatment, adequately counsel patients regarding risks and benefits, and formulate an appropriate follow-up plan.

Contraceptive options for women with premenstrual dysphoric disorder: current insights and a narrative review.

Premenstrual syndrome and its most severe form, premenstrual dysphoric disorder (PMDD), are two well-defined clinical entities that affect a considerable number of women. Progesterone metabolites and certain neurotransmitters, such as gamma-aminobutyric acid and serotonin, are involved in the etiology of this condition. Until recently, the only treatment for women with PMDD was psychoactive drugs, such as selective serotonin reuptake inhibitors. Several years ago, there has been evidence of the beneficial role of combined hormonal contraceptives in controlling PMDD symptoms. Oral combined hormonal contraceptives that contain drospirenone in a 24+4-day regimen are the only drugs that have been approved by US Food and Drug Administration for the treatment of PMDD, but there is scientific evidence that other agents, with other formulations and regimens, could also be effective for the treatment of this condition. However, it remains unclear whether the beneficial effect of combined hormonal contraceptives is associated with the type of estrogen or progestogen used or the treatment regimen.

Non-Contraceptive Benefits of Oral Hormonal Contraceptives

It is becoming evident that oral hormonal contraceptives-besides being well established contraceptives-seem to become important medications for many functional or organic disturbances. So far, clinical effectiveness has been shown for treatment as well as prevention of menstrual bleeding disorders and menstrual-related pain symptoms. Also this is true for premenstrual syndrome (PMS) and premenstrual disphoric disorder (PMDD).Particular oral contraceptives (OCs) containing anti-androgenic progestogens were shown to be effective medications for treatment of androgenisation symptoms (seborrhea, acne, hirsutism, alopecia).Through perfect suppression of the hypothalamic-pituitary-ovarian axis OCs have proven to be effective in elimination of persistent follicular cysts. Endometriosis/adenomyosis related pain symptoms are well handled similar to other drugs like Gonadotropine Releasing Hormone agonists but are less expensive, with less side effects, and possibility to be used for longer periods of time. This is also true for myoma. Pelvic inflammatory disease, rheumatoid arthritis, menstrual migraine, and onset of multiple sclerosis are prevented or delayed. Bone density is preserved and asthma symptoms improved. Endometrial hyperplasia and benign breast disease can be controlled. There is definitely a significant impact on risk reduction regarding endometrial, ovarian, and colon cancers.In conclusion, it needs to be recognized that oral combined hormonal contraceptives (estrogen/ progestogen combination) are - besides being reliable forms of contraception - are cost-effective medications for many medical disorders in women. Therefore, these contraceptives drugs are important for female and global health and should be used in clinical practice.

A select issue in the postpartum period: contraception

A select issue in the postpartum period: contraception

Evaluation of lipid profile in adolescents during long-term use of combined oral hormonal contraceptives

The study evaluated the effects of the long-term use of a combined oral hormonal contraceptive containing 30 μg ethinyl estradiol and 75 μg gestodene in adolescents. Thirty-three volunteers, aged from 14 to 19 years, who used the oral contraceptive for three consecutive years, were studied. Evaluation of total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides was made before use and after 1, 2 and 3 years. During the 3-year study period, total cholesterol, HDL-C, LDL-C and triglyceride levels were significantly higher than previous measurements, but average values did not exceed the normal range. Compared to the first year, the second- and third-year cholesterol, HDL-C, LDL-C and triglyceride levels were not significantly different.

The use of combined oral hormonal contraceptives (COCs) is "still quite low" among women in Shanghai, China,

The use of combined oral hormonal contraceptives (COCs) is "still quite low" among women in Shanghai, China,

The acceptability of combined oral hormonal contraceptives in Shanghai, People’s Republic of China

Although combined oral hormonal contraceptives have been described as the most significant medical advance of the 20th century, the usage rate in the People’s Republic of China is considerably lower than in developed countries. This survey aimed to explore the acceptability of combined oral hormonal contraceptives (COC) amongst women aged 18–35 years who attended the family planning clinic in the International Peace Maternity and Child Health Hospital in Shanghai, as well as amongst gynecologists who worked in the same hospital. In total, 500 clients and 89 gynecologists were recruited. Only 12% of the clients had ever used COC. Women with a lower educational level or parous women were more likely to use COC (p < 0.05). COC was the third most popular method recommended by the gynecologists (85.4%). Both groups were concerned about the risks and side effects of COC, especially younger doctors and doctors with fewer years of experience (p < 0.01). The results of the survey suggest that it is necessary to provide improved training about COC to reproductive-aged women and professionals to dispel misunderstandings of the pill.