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1.  The association between drospirenone and hyperkalemia: a comparative-safety study 
Drospirenone/ethinyl-estradiol is an oral contraceptive (OC) that possesses unique antimineralocorticoid activity. It is conjectured that drospirenone, taken alone or concomitantly with spironolactone, may be associated with an increased risk of hyperkalemia.
A retrospective cohort study was conducted evaluating women between 18-46 years of age in the Lifelink™ Health Plan Claims Database. The study was restricted to new users of OCs between 1997-2009. Cox proportional hazards models were used to estimate the time to first occurrence of hyperkalemia diagnosis. The main analysis compared OCs containing drospirenone with OCs containing levonorgestrel, a second generation OC not known to impact potassium homeostasis. Logistic regression evaluated concomitant prescribing of drospirenone and spironolactone
The cohort included 1,148,183 women, averaging 28.8 years of age and 280 days of OC therapy. 2325 cases of hyperkalemia were identified. The adjusted hazard ratio (HR) for hyperkalemia with drospirenone compared to levonorgestrel was 1.10 (95%CI 0.95-1.26). There was an increased risk of hyperkalemia with norethindrone HR 1.15 (95%CI: 1.00-1.33) and norgestimate HR 1.27 (95%CI: 1.11-1.46). Other OCs were unassociated with hyperkalemia. The odds of receiving spironolactone while taking drospirenone were 2.66 (95%CI 2.53-2.80) times higher than the odds of receiving spironolactone and levonorgestrel. Only 6.5% of patients taking drospirenone and spironolactone had a serum potassium assay within 180 days of starting concomitant therapy.
A clinically significant signal for hyperkalemia with drospirenone was not demonstrated in the current study. Despite the bolded warning for hyperkalemia with joint drospirenone and spironolactone administration, physicians are actually using them together preferentially, and are not following the recommended potassium monitoring requirements in the package insert.
PMCID: PMC3265420  PMID: 22208934
2.  Risk of venous thromboembolism in women with polycystic ovary syndrome: a population-based matched cohort analysis 
There is an increased risk of venous thromboembolism among women taking oral contraceptives. However, whether there is an additional risk among women with polycystic ovary syndrome (PCOS) is unknown.
We developed a population-based cohort from the IMS LifeLink Health Plan Claims Database, which includes managed care organizations in the United States. Women aged 18–46 years taking combined oral contraceptives and who had a claim for PCOS (n = 43 506) were matched, based on a propensity score, to control women (n = 43 506) taking oral contraceptives. Venous thromboembolism was defined using administrative coding and use of anticoagulation. We used Cox proportional hazards models to assess the relative risk (RR) of venous thromboembolism among users of combined oral contraceptives with and without PCOS.
The incidence of venous thromboembolism among women with PCOS was 23.7/10 000 person-years, while that for matched controls was 10.9/10 000 person-years. Women with PCOS taking combined oral contraceptives had an RR for venous thromboembolism of 2.14 (95% confidence interval [CI] 1.41–3.24) compared with other contraceptive users. The incidence of venous thromboembolism was 6.3/10 000 person-years among women with PCOS not taking oral contraceptives; the incidence was 4.1/10 000 person-years among matched controls. The RR of venous thromboembolism among women with PCOS not taking oral contraceptives was 1.55 (95% CI 1.10–2.19).
We found a 2-fold increased risk of venous thromboembolism among women with PCOS who were taking combined oral contraceptives and a 1.5-fold increased risk among women with PCOS not taking oral contraceptives. Physicians should consider the increased risk of venous thromboembolism when prescribing contraceptive therapy to women with PCOS.
PMCID: PMC3563911  PMID: 23209115
3.  Drospirenone/ethinyl estradiol 3 mg/20 μg (24/4 day regimen): hormonal contraceptive choices – use of a fourth-generation progestin 
The combined oral contraceptive pill (COC) consisting of drospirenone 3 mg/ethinyl estradiol 20 μg (3 mg DRSP/20 μg EE-24/4) supplies 24 days of pills with hormones followed by 4 days of hormone-free pills. This regimen is called the 24/4 regimen. The progesterone component of this oral contraceptive pill (OCP), drospirenone (DRSP), is a fourth-generation progestin that has potent progestogenic, antimineralocorticoid, and antiandrogenic activity, which are unique characteristics compared with the other progestogens contained in most of the other OCPs currently marketed. This formulation, in addition to being an effective long-term OCP, has the additional medical benefit of providing a good parallel treatment for premenstrual dysphoric disorder and moderate acne. The effectiveness of 3 mg DRSP/20 μg EE-24/4, its tolerability and safety, and its additional non-contraceptive benefits are discussed.
PMCID: PMC2778416  PMID: 19936169
drospirenone; premenstrual dysphoric disorder; acne vulgaris; contraception; antimineralocorticoid activity; antiandrogenic activity
4.  Effect of progestin vs. combined oral contraceptive pills on lactation: A double-blind randomized controlled trial 
Obstetrics and gynecology  2012;119(1):5-13.
To estimate the effect of progestin-only vs. combined hormonal contraceptive pills on rates of breastfeeding continuation in postpartum women. Secondary outcomes include infant growth parameters, contraceptive method continuation and patient satisfaction with breastfeeding and contraceptive method.
In this randomized controlled trial, postpartum breastfeeding women who desired oral contraceptives were assigned to progestin-only vs. combined hormonal contraceptive pills. At two and eight weeks postpartum, participants completed in-person questionnaires that assessed breastfeeding continuation and contraceptive use. Infant growth parameters including weight, length and head circumference were assessed at eight weeks postpartum. Telephone questionnaires assessing breastfeeding, contraceptive continuation and satisfaction were completed at 3-7 weeks and 4 and 6 months. Breastfeeding continuation was compared between groups using Cox proportional hazards regression. Differences in baseline demographic characteristics and in variables between the two intervention groups were compared using chi-square tests, Fisher’s Exact test, or two-sample t-tests as appropriate.
Breastfeeding continuation rates, contraceptive continuation, and infant growth parameters did not differ between users of progestin-only and combined hormonal contraceptive pills. Infant formula supplementation and maternal perception of inadequate milk supply were associated with decreased rates of breastfeeding in both groups.
Choice of combined or progestin-only birth control pills administered two weeks postpartum did not adversely affect breastfeeding continuation.
PMCID: PMC3586805  PMID: 22143258
5.  Safety, efficacy, actions, and patient acceptability of drospirenone/ethinyl estradiol contraceptive pills in the treatment of premenstrual dysphoric disorder 
Premenstrual dysphoric disorder (PMDD) is estimated to affect 3%–8% of reproductive age women. Multiple therapeutic modalities have been evaluated with varying efficacy for the associated somatic and mood symptoms. The majority of older studies had shown that oral contraceptive pills (OCs) were most effective for the physical symptoms. However, newer OCs containing a novel progestin, drospirenone, have shown promise in alleviating both the somatic and affective/behavioral symptoms. This progestin, which is a derivative of spironolactone, has both antimineralocorticoid and antiandrogenic activity. A 24/4 formulation containing 20 μg of ethinyl estradiol has been found effective in randomized double-blind placebo-controlled trials utilizing established scales documenting symptoms associated with PMDD. Multiple studies have shown that drospirenone-containing OCs are safe without evidence of clinically adverse effects on carbohydrate metabolism, lipids, blood pressure, weight, serum potassium or increased thrombotic events compared to other low dose OCs. In addition, significant improvements have been demonstrated in acne, hirsutism, and fluid retention symptoms. Several open label studies demonstrated good patient compliance and reported satisfaction with the method. Because of the significant placebo effect demonstrated in the blinded placebo-controlled trials, additional large randomized placebo-controlled trials are needed to confirm the efficacy of the drospirenone OCs in the treatment of PMDD. However, this OC formulation appears to be a promising therapeutic modality.
PMCID: PMC2971718  PMID: 21072278
drospirenone; premenstrual dysphoric disorder; premenstrual syndrome; oral contraceptive pill
6.  Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: case-control study using United States claims data 
Objective To compare the risk of non-fatal venous thromboembolism in women receiving oral contraceptives containing drospirenone with that in women receiving oral contraceptives containing levonorgestrel.
Design Nested case-control and cohort study.
Setting The study was based on information from PharMetrics, a United States based company that collects information on claims paid by managed care plans.
Participants The study encompassed all women aged 15 to 44 years who received an oral contraceptive containing either drospirenone or levonorgestrel after 1 January 2002. Cases were women with current use of a study oral contraceptive and a diagnosis of venous thromboembolism in the absence of identifiable clinical risk factors (idiopathic venous thromboembolism). Up to four controls were matched to each case by age and calendar time.
Main outcome measures Odds ratios comparing the risk of non-fatal venous thromboembolism in users of the two contraceptives; incidence rates and rate ratios of non-fatal venous thromboembolism for users of each of the study contraceptives.
Results 186 newly diagnosed, idiopathic cases of venous thromboembolism were identified in the study population and matched with 681 controls. In the case-control analysis, the conditional odds ratio for venous thromboembolism comparing use of oral contraceptives containing drospirenone with use of those containing levonorgestrel was 2.3 (95% confidence interval 1.6 to 3.2). The incidence rates for venous thromboembolism in the study population were 30.8 (95% confidence interval 25.6 to 36.8) per 100 000 woman years among users of oral contraceptives containing drospirenone and 12.5 (9.61 to 15.9) per 100 000 woman years among users of oral contraceptives containing levonorgestrel. The age adjusted incidence rate ratio for venous thromboembolism for current use of oral contraceptives containing drospirenone compared with those containing levonorgestrel was 2.8 (2.1 to 3.8).
Conclusions The risk of non-fatal venous thromboembolism among users of oral contraceptives containing drospirenone seems to be around twice that of users of oral contraceptives containing levonorgestrel, after the effects of potential confounders and prescribing biases have been taken into account.
PMCID: PMC3081040  PMID: 21511805
7.  Breast cancer and specific types of combined oral contraceptives. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives. 
British Journal of Cancer  1992;65(1):108-113.
Data on 2,754 cases and 18,565 controls from a multinational hospital-based, case-control study were analysed to determine whether observed associations between combined oral contraceptives and breast cancer are similar for oral contraceptives with varying types and doses of oestrogens and progestins. After stratifying on duration of use, risk was found to be increased in current and recent users, and to decline with time since last use. These associations, of similar strength, were observed for users of products that contain mestranol and ethinyl estradiol, for women who used preparations with progestins derived from 19-nortestosterone and 17-alpha-hydroxyprogesterone, and for those who took preparations with relatively higher and lower doses of oestrogen. When products with equal doses of the same oestrogen or progestin and varying doses of the other hormonal constituent were considered, slightly higher relative risks per year of use were estimated for users of products with relatively higher than lower doses of either the constituent oestrogen or progestin, but the differences in relative risk could readily have occurred by chance. This study provides no evidence that risk of breast cancer in users of oral contraceptives varies by the type of oestrogen or progestin consumed.
PMCID: PMC1977361  PMID: 1733433
8.  Oral contraceptive use, iron stores, and vascular endothelial function in healthy women 
Contraception  2011;84(3):285-290.
Increased iron stores are associated with greater cardiovascular risk in post-menopausal women. Oral contraceptive pill (OCP) use decreases the volume of menstrual blood loss and increases iron stores, but the link between OCP use, iron stores, and cardiovascular risk in pre-menopausal women has not been characterized.
Study Design
We conducted a cross-sectional study of 23 healthy OCP users to determine the association between type and duration of OCP exposure, iron stores, and vascular endothelial function [flow-mediated dilation (FMD) in the brachial artery].
Median duration of OCP use was 45 months. FMD in the brachial artery was significantly associated with progestin type used (estranes/gonanes vs. drospirenone) and duration of OCP use (both p<0.05) but not iron stores. In multivariate analysis, progestin type was the only independent predictor of FMD.
Use of OCP containing drospirenone was independently associated with greater FMD in the brachial artery, and thus a potentially more favorable cardiovascular risk profile, when compared with use of OCP containing estranes/gonanes.
PMCID: PMC3285555  PMID: 21843695
oral contraceptive pills; progestins; vascular endothelium; iron
9.  Use of ethinylestradiol/drospirenone combination in patients with the polycystic ovary syndrome 
Polycystic ovary syndrome (PCOS) is one of the most common endocrine/metabolic disorders found in women, affecting approximately 105 million women worldwide. It is characterized by ovulatory dysfunction, often presenting as oligomenorrhea or amenorrhea and either clinical or biochemical hyperandrogenism. Combined oral contraceptive (COC) therapy has long been a cornerstone of care for women with PCOS. COC therapy often provides clinical improvement in the areas of excessive hair growth, unpredictable menses, acne, and weight gain. One of the main issues in COC therapy is choosing the most appropriate progestin component to provide the greatest anti androgenic effects. Drospirenone, a relatively new progestin, has shown benefit in the PCOS population when used in conjunction with ethinyl estradiol. We now review the role of COCs in PCOS, focusing specifically on drospirenone. Controversy over metabolic effects of COCs in PCOS is also discussed.
PMCID: PMC2504056  PMID: 18728832
polycystic ovary syndrome; PCOS; oral contraceptives; drospirenone; treatment
10.  Gallbladder disease and use of transdermal versus oral hormone replacement therapy in postmenopausal women: prospective cohort study 
Objective To determine whether transdermal compared with oral use of hormone replacement therapy reduces the risk of gallbladder disease in postmenopausal women.
Design Prospective cohort study (Million Women Study).
Setting Women registered with the National Health Service (NHS) in England and Scotland.
Participants 1 001 391 postmenopausal women (mean age 56) recruited between 1996 and 2001 from NHS breast screening centres and followed by record linkage to routinely collected NHS hospital admission data for gallbladder disease.
Main outcome measures Adjusted relative risk and standardised incidence rates of hospital admission for gallbladder disease or cholecystectomy according to use of hormone replacement therapy.
Results During follow-up 19 889 women were admitted for gallbladder disease; 17 190 (86%) had a cholecystectomy. Compared with never users of hormone replacement therapy, current users were more likely to be admitted for gallbladder disease (relative risk 1.64, 95% confidence interval 1.58 to 1.69) but risks were substantially lower with transdermal therapy than with oral therapy (relative risk 1.17, 1.10 to 1.24 v 1.74, 1.68 to 1.80; heterogeneity P<0.001). Among women using oral therapy, equine oestrogens were associated with a slightly greater risk of gallbladder disease than estradiol (relative risk 1.79, 1.72 to 1.87 v 1.62, 1.54 to 1.70; heterogeneity P<0.001) and higher doses of oestrogen increased the risk more than lower doses: for equine oestrogens >0.625 mg, 1.91 (1.78 to 2.04) v ≤0.625 mg, 1.76 (1.68 to 1.84); heterogeneity P=0.02; estradiol >1 mg, 1.68 (1.59 to 1.77) v ≤1 mg, 1.44 (1.31 to 1.59); heterogeneity P=0.003. The risk of gallbladder disease decreased with time since stopping therapy (trend P=0.004). Results were similar taking cholecystectomy as the outcome. Standardised hospital admission rates per 100 women over five years for cholecystectomy were 1.1 in never users, 1.3 with transdermal therapy, and 2.0 with oral therapy.
Conclusion Gallbladder disease is common in postmenopausal women and use of hormone replacement therapy increases the risk. Use of transdermal therapy rather than oral therapy over a five year period could avoid one cholecystectomy in every 140 users.
PMCID: PMC2500203  PMID: 18617493
11.  Investigation of the Hemostatic Effect of a Transdermal Patch Containing 0.55 mg Ethinyl Estradiol and 2.1 mg Gestodene Compared with a Monophasic Oral Contraceptive Containing 0.03 mg Ethinyl Estradiol and 0.15 mg Levonorgestrel: An Open-Label, Randomized, Crossover Study 
Drugs in R&d  2013;13:223-233.
Transdermal delivery of contraceptives offers several advantages over combined oral contraceptives (COCs), including effective absorption and the provision of relatively constant serum concentrations. Ethinyl estradiol (EE) and the progestin gestodene are well-absorbed through the skin and, therefore, well-suited for use in a transdermal contraceptive patch.
The objective of this study was to investigate the impact of a once-weekly transparent, transdermal patch delivering low doses of EE and gestodene equivalent to a COC containing 0.02 mg EE and 0.06 mg gestodene on hemostasis parameters compared with a monophasic COC containing 0.03 mg EE and 0.15 mg levonorgestrel.
In this single-center, open-label, randomized, crossover study, 30 women (aged 18–35 years) received three cycles of each treatment, separated by a two-cycle washout period. The primary outcome measure was the absolute change from baseline in prothrombin fragments 1 + 2 and d-dimer.
For both treatments, prothrombin fragments 1 + 2 remained stable during the first treatment period, and increased only slightly in the second period (mean absolute change 0.025 and 0.028 nmol/L in the novel Bayer patch and COC groups, respectively). Increases in d-dimer were observed in both periods (mean absolute change 107.0 ± 147.2 ng/L for the novel Bayer patch and 113.7 ± 159.0 ng/L for the COC). There were no statistically significant treatment differences in prothrombin 1 + 2 or d-dimer (p = 0.667 and p = 0.884, respectively) and no statistically significant treatment sequence or period effects.
A COC containing 0.03 mg EE and 0.15 mg levonorgestrel and the novel Bayer patch have comparable influence on hemostatic endpoints. Both treatments were well-tolerated by subjects.
PMCID: PMC3784047  PMID: 24043457
12.  Hormonal Contraception and Thrombotic Risk: A Multidisciplinary Approach 
Pediatrics  2011;127(2):347-357.
Heightened publicity about hormonal contraception and thrombosis risk and the publication of new guidelines by the World Health Organization in 2009 and the Centers for Disease Control and Prevention in 2010 addressing this complex issue have led to multidisciplinary discussions on the special issues of adolescents cared for at our pediatric hospital. In this review of the literature and new guidelines, we have outlined our approach to the complex patients referred to our center. The relative risk of thrombosis on combined oral contraception is three- to fivefold, whereas the absolute risk for a healthy adolescent on this therapy is only 0.05% per year. This thrombotic risk is affected by estrogen dose, type of progestin, mechanism of delivery, and length of therapy. Oral progestin-only contraceptives and transdermal estradiol used for hormone replacement carry minimal or no thrombotic risk. Transdermal, vaginal, or intrauterine contraceptives and injectable progestins need further study. A personal history of thrombosis, persistent or inherited thrombophilia, and numerous lifestyle choices also influence thrombotic risk. In this summary of one hospital's approach to hormone therapies and thrombosis risk, we review relative-risk data and discuss the application of absolute risk to individual patient counseling. We outline our approach to challenging patients with a history of thrombosis, known thrombophilia, current anticoagulation, or family history of thrombosis or thrombophilia. Our multidisciplinary group has found that knowledge of the guidelines and individualized management plans have been particularly useful for informing discussions about hormonal and nonhormonal options across varied indications.
PMCID: PMC3025417  PMID: 21199853
contraception; thrombosis; thrombophilia; hormone
13.  Matched-pairs analysis of ovarian suppression during oral versus vaginal hormonal contraceptive use 
Contraception  2011;84(5):e1-e4.
This study was conducted to compare ovarian suppression during oral versus vaginal hormonal contraceptive use. Secondary aims included comparison of endometrial thickness and bleeding patterns.
In two open-label trials assessing ovarian suppression, 33 compliant women completed both studies. They first used OCs [randomized to either 20 mcg ethinyl estradiol (EE)/100 mcg levonorgestrel (LNG) or 30 mcg EE/150 mcg LNG] and subsequently used contraceptive vaginal rings (CVR) (daily release of 15 mcg EE/120 mcg etonogestrel), all 21/7 day regimens. Participants had at least one run-in cycle using each contraceptive method prior to evaluation. During one cycle of each method, women underwent bi-weekly transvaginal sonography to measure ovarian follicular diameters and endometrial thickness. We also noted presence of a corpus luteum or a ruptured follicle as a marker of ovulation. Participants recorded bleeding days on paper calendars. We used matched pairs analyses as appropriate.
During follow-up, we identified at least one ovarian follicle ≥8 mm in 20/33 (61%) OC users and 12/33 (36%) CVR users (matched pairs analysis, p=0.02). Similar trends were seen for larger follicles; however we had limited statistical power to evaluate these differences. Median follicular diameter among OC users was larger than median follicular diameter among CVR users (p=0.01). We did not observe a corpus luteum or ruptured follicle in any participant during either study. Endometrial thickness was similar during OC and CVR use (mean 4.1 ± 1.4 mm versus 4.1 ± 1.6 mm, p=0.9) as was the number of bleeding or spotting days (mean 2.1 ± 2.4 versus 1.9 ± 2.1, p=0.8). OC dose was unrelated to follicle diameter, endometrial thickness, or bleeding.
Ovarian follicles ≥8 mm were more common in 33 compliant women during OC use than during CVR use indicating CVR use results in greater ovarian suppression than OC use.
PMCID: PMC3201769  PMID: 22018131
NuvaRing®; Oral Contraception; Ovarian Suppression
14.  Studies on the mechanism of non-visualization of diseased human gallbladders during oral cholecystography. 
Postgraduate Medical Journal  1988;64(758):931-934.
Oral cholecystography is a well established method for studying the human gallbladder and radiological non-visualization of the gallbladder has been shown to correlate highly with the presence of disease. The exact mechanism by which diseased gallbladders fail to visualize is unclear, but may be due to a failure of the gallbladder to concentrate the luminal contents. Concentration of gallbladder contents is achieved by the reabsorption of water, the driving force for which is active sodium (Na+) absorption. Therefore Na+ transport was studied by measuring the flux of Na22 across isolated human gallbladder mucosa (obtained at cholecystectomy) and compared with the results of oral cholecystography and histological grading. In 27 gallbladders studied, 59% absorbed Na+, whilst the remainder secreted Na+. Comparison with histological grading showed that as gallbladders became more diseased they absorbed less Na+ and were more likely to secrete Na+. In addition, gallbladders that absorbed Na+ were significantly more likely to visualize on cholecystography than those that secreted Na+. These results indicate that some diseased human gallbladders secrete, rather than absorb, Na+ and suggest that the mechanism for radiological non-visualization is failure of fluid absorption and the development of active fluid secretion.
PMCID: PMC2429087  PMID: 2855753
15.  Effect of hormonal contraceptive use on HIV progression in female HIV seroconverters in Rakai, Uganda 
AIDS (London, England)  2010;24(12):1937-1944.
To assess the association between hormonal contraceptive use and HIV progression.
A retrospective analysis of 625 female HIV seroconverters from a Ugandan cohort study.
Multivariate Cox regression analyses incorporating time-varying hormonal contraceptive exposure were used to estimate the adjusted hazard ratios of death, and a composite outcome of AIDS or death, associated with hormonal contraceptive use. Sensitivity analyses included lagging hormonal contraceptive exposure, varying comparison groups, and separately assessing effects of oral and injectable contraceptives.
A total of 27.5% of women reported ever using hormonal contraception. Of 625 women, 104 (16.6%) died and 291 (46.6%) progressed to AIDS or death during observation. Time-varying hormonal contraceptive use was not associated with an increased hazard of death as compared with nonuse of hormonal contraception (adjusted hazard ratio 0.76, 95% confidence interval 0.41–1.39, P = 0.37), and was associated with a significantly reduced hazard of progression to AIDS or death (adjusted hazard ratio 0.70, 95% confidence interval 0.50–0.97, P = 0.03). None of the sensitivity analyses suggested an adverse effect of hormonal contraception on HIV progression.
Hormonal contraceptive use was not associated with faster progression to death, and was associated with a reduced hazard of progression to the composite outcome of AIDS or death.
PMCID: PMC2939866  PMID: 20502314
family planning; HIV progression; hormonal contraception; survival analysis; Uganda
16.  EE-drospirenone-levomefolate calcium versus EE-drospirenone + folic acid: folate status during 24 weeks of treatment and over 20 weeks following treatment cessation 
Adequate folate supplementation in the periconceptional phase is recommended to reduce the risk of neural tube defects. Oral contraceptives may provide a reasonable delivery vehicle for folate supplementation before conception in women of childbearing potential. This study aimed to demonstrate that a fixed-dose combination of an oral contraceptive and levomefolate calcium leads to sustainable improvements in folate status compared with an oral contraceptive + folic acid.
This was a double-blind, randomized, parallel-group study in which 172 healthy women aged 18–40 years received ethinylestradiol (EE)-drospirenone-levomefolate calcium or EE-drospirenone + folic acid for 24 weeks (invasion phase), and EE-drospirenone for an additional 20 weeks (folate elimination phase). The main objective of the invasion phase was to examine the area under the folate concentration time-curve for plasma and red blood cell (RBC) folate, while the main objective of the elimination phase was to determine the duration of time for which RBC folate concentration remained ≥ 906 nmol/L after cessation of EE-drospirenone-levomefolate calcium.
Mean concentration-time curves for plasma folate, RBC folate, and homocysteine were comparable between treatment groups during both study phases. During the invasion phase, plasma and RBC folate concentrations increased and approached steady-state after about 8 weeks (plasma) or 24 weeks (RBC). After cessation of treatment with levomefolate calcium, folate concentrations decreased slowly. The median time to RBC folate concentrations falling below 906 nmol/L was 10 weeks (95% confidence interval 8–12 weeks) after cessation of EE-drospirenone-levomefolate calcium treatment. Plasma and RBC folate levels remained above baseline values in 41.3% and 89.3% of women, respectively, at the end of the 20-week elimination phase.
Improvements in folate status were comparable between EE-drospirenone-levomefolate calcium and EE-drospirenone + folic acid. Plasma and RBC folate levels remained elevated for several months following cessation of treatment with EE-drospirenone-levomefolate calcium.
PMCID: PMC3628530  PMID: 23610531
drospirenone; ethinylestradiol; folic acid; levomefolate calcium; neural tube defect; oral contraception
17.  Oral contraceptive use and reproductive factors and risk of ovarian cancer in the European Prospective Investigation into Cancer and Nutrition 
British Journal of Cancer  2011;105(9):1436-1442.
It is well established that parity and use of oral contraceptives reduce the risk of ovarian cancer, but the associations with other reproductive variables are less clear.
We examined the associations of oral contraceptive use and reproductive factors with ovarian cancer risk in the European Prospective Investigation into Cancer and Nutrition. Among 327 396 eligible women, 878 developed ovarian cancer over an average of 9 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models stratified by centre and age, and adjusted for smoking status, body mass index, unilateral ovariectomy, simple hysterectomy, menopausal hormone therapy, and mutually adjusted for age at menarche, age at menopause, number of full-term pregnancies and duration of oral contraceptive use.
Women who used oral contraceptives for 10 or more years had a significant 45% (HR, 0.55; 95% CI, 0.41–0.75) lower risk compared with users of 1 year or less (P-trend, <0.01). Compared with nulliparous women, parous women had a 29% (HR, 0.71; 95% CI, 0.59–0.87) lower risk, with an 8% reduction in risk for each additional pregnancy. A high age at menopause was associated with a higher risk of ovarian cancer (>52 vs ⩽45 years: HR, 1.46; 95% CI, 1.06–1.99; P-trend, 0.02). Age at menarche, age at first full-term pregnancy, incomplete pregnancies and breastfeeding were not associated with risk.
This study shows a strong protective association of oral contraceptives and parity with ovarian cancer risk, a higher risk with a late age at menopause, and no association with other reproductive factors.
PMCID: PMC3241548  PMID: 21915124
reproductive history; oral contraceptive use; ovarian cancer; cohort study
18.  Effects of Oral, Vaginal, and Transdermal Hormonal Contraception on Serum Levels of Coenzyme Q10, Vitamin E, and Total Antioxidant Activity 
The use of the transdermal contraceptive patch is associated with greater bioavailability of ethinyl estradiol (EE) compared with contraceptive vaginal ring or oral contraceptives (OC). We compared the influences of three contraceptive methods (OC, vaginal ring, and transdermal patch) on serum levels of coenzyme Q10, α-tocopherol, γ-tocopherol and total antioxidant capacity in premenopausal women. Blood samples from 30 premenopausal women who used hormonal contraception for at least 4 months were collected. Forty subjects who did not use any contraception were studied as control. Serum levels of coenzyme Q10, α-tocopherol and γ-tocopherol were measured by high-pressure liquid chromatography. Serum samples were also assayed for total antioxidant capacity (TAOC). Serum levels of coenzyme Q10 and α-tocopherol were found to be significantly lower (P < .05) in all three contraceptive users compared with controls. Contraceptive patch users had the lowest levels of coenzyme Q10 levels compared with normal subjects. Serum TAOC levels were significantly lower (P < .05) among the contraceptive user groups. Alterations in coenzyme Q10 and α-tocopherol induced by hormonal contraception and the potential effect(s) of exogenous ovarian hormones should be taken into consideration in future antioxidant research.
PMCID: PMC2929620  PMID: 20814444
19.  Nomegestrol acetate-17b-estradiol for oral contraception 
Oral contraceptives remain a popular method of contraception over 50 years after their introduction. While safe and effective for many women, the failure rate of oral contraception is about 8%. Concerns about the risk of venous thromboembolism continue to drive the search for the safest oral contraceptive formulations. The oral contraceptive NOMAC-E2 contains nomegestrol acetate (NOMAC) 2.5 mg + 17b-estradiol (E2) 1.5 mg. The approved dosing regimen is 24 days of active hormone, followed by a 4-day hormone-free interval. NOMAC is a progestin derived from testosterone, which has high bioavailability, rapid absorption, and a long half-life. Estradiol, though it has a lower bioavailability, has been successfully combined with NOMAC in a monophasic oral contraceptive. Two recently published randomized controlled trials demonstrate that NOMAC-E2 is an effective contraceptive, with a Pearl Index less than one pregnancy per 100 woman-years. The bleeding pattern on NOMAC-E2 is characterized by fewer bleeding/spotting days, shorter withdrawal bleeds, and a higher incidence of amenorrhea than the comparator oral contraceptive containing drospirenone and ethinyl estradiol. The adverse event profile appears to be acceptable. Few severe adverse events were reported in the randomized controlled trials. The most common adverse events were irregular bleeding, acne, and weight gain. Preliminary studies suggest that NOMAC-E2 does not seem to have negative effects on hemostatic and metabolic parameters. While no one oral contraceptive formulation is likely to be the optimum choice for all women, NOMAC-E2 is a formulation with effectiveness comparable with that of other oral contraceptives, and a reassuring safety profile.
PMCID: PMC3702550  PMID: 23836965
oral contraception; nomegestrol acetate; estradiol
20.  Geographic variation of gallbladder cancer mortality and risk factors in Chile: a population-based ecologic study 
Chile’s gallbladder cancer rates are among the highest in the world, being the first cancer killer among Chilean women. To provide insights into the etiology of gallbladder cancer, we conducted an ecologic study examining the geographical variation of gallbladder cancer and several putative risk factors. The relative risk of dying from gallbladder cancer (relative to the national average mortality rate) between 1985 and 2003 was estimated for each of the 333 Chilean counties, using a hierarchical Poisson regression model, adjusting for age, sex, and geographical location. The risk of gallbladder cancer mortality was analyzed in relation to region (costal, inland, northern, and southern), poverty, Amerindian (Mapuche) population, typhoid fever, and access to cholecystectomy, using logistic regression analysis. There were 27,183 gallbladder cancer deaths, age-sex-adjusted county mortality rates ranging from 8.2 to 12.4 per 100,000 inhabitants, being higher in inland and southern regions; compare to the north-coastal, the northern-inland region had a 10-fold risk odds ratio (OR) (95% of confidence interval (95% CI): 2.4–42.2) and the southern-inland region had a 26-fold risk (OR 95%CI: 6.0–114.2). Independent risk factors for gallbladder cancer were: ethnicity (Mapuche) OR:3.9 (95%CI 1.8–8.7), typhoid fever OR:2.9 (95%CI 1.2–6.9), poverty OR:5.1 (95%CI 1.6–15.9), low access to cholecystectomy OR:3.9 (95%CI 1.5–10.1), low access to hospital care OR:14.2 (95%CI 4.2–48.7) and high urbanization OR:8.0 (95%CI 3.4–18.7). Our results suggest that gallbladder cancer in Chile may be related to both genetic factors and poor living conditions. Future analytic studies are needed to further clarify the role of these factors in gallbladder cancer etiology.
PMCID: PMC2864002  PMID: 18566990
gallbladder cancer; gallstones; Mapuche; typhoid; genetics
21.  Risk of venous thromboembolism among users of third generation oral contraceptives compared with users of oral contraceptives with levonorgestrel before and after 1995: cohort and case-control analysis 
BMJ : British Medical Journal  2000;321(7270):1190-1195.
To compare the risk of idiopathic venous thromboembolism among women taking third generation oral contraceptives (with gestodene or desogestrel) with that among women taking oral contraceptives with levonorgestrel.
Cohort and case-control analyses derived from the General Practice Research Database.
UK general practices, January 1993 to December 1999.
Women aged 15-39 taking third generation oral contraceptives or oral contraceptives with levonorgestrel.
Main outcome measures
Relative incidence (cohort study) and odds ratios (case-control study) as measures of the relative risk of venous thromboembolism.
The adjusted estimates of relative risk for venous thromboembolism associated with third generation oral contraceptives compared with oral contraceptives with levonorgestrel was 1.9 (95% confidence interval 1.3 to 2.8) in the cohort analysis and 2.3 (1.3 to 3.9) in the case-control study. The estimates for the two types of oral contraceptives were similar before and after the warning issued by the Committee on Safety of Medicines in October 1995. A shift away from the use of third generation oral contraceptives after the scare was more pronounced among younger women (who have a lower risk of venous thromboembolism) than among older women. Fewer cases of venous thromboembolism occurred in 1996 and later than would have been expected if the use of oral contraceptives had remained unchanged.
These findings are consistent with previously reported studies, which found that compared with oral contraceptives with levonorgestrel, third generation oral contraceptives are associated with around twice the risk of venous thromboembolism.
PMCID: PMC27524  PMID: 11073511
22.  Combining oral contraceptives with a natural nuclear factor-kappa B inhibitor for the treatment of endometriosis-related pain 
Endometriosis is a chronic disease in which a persistent state of heightened inflammation is maintained by nuclear factor-kappa B (NF-κB) activation. The progestins present in oral contraceptives are potent inhibitors of NF-κB translocation to cell nuclei, while Pycnogenol® (Pinus pinaster) acts by blocking post-translational events. In this study, the effects of Pycnogenol on pain scores were investigated in patients with endometriosis using oral contraceptives containing either gestodene or drospirenone in extended regimens. Pain scores were determined using a visual analog scale before and after 3 months of treatment. Oral contraceptives, used alone (groups 1 and 3) or in association with Pycnogenol (groups 2 and 4), resulted in significant decreases in pain scores after 3 months of treatment; however, this reduction was significantly greater in the groups using oral contraceptives + Pycnogenol (groups 2 and 4) compared with those using oral contraceptives alone (groups 1 and 3). In the groups using oral contraceptives alone, 50% of patients became pain-free by the end of the third month of treatment. These results suggest that Pycnogenol increases the efficacy of oral contraceptives for the treatment of endometriosis-related pain.
PMCID: PMC3873204  PMID: 24379702
Pycnogenol®; aromatase; endometriosis; nuclear factor-kappa B
23.  Assessing the risk of venous thromboembolic events in women taking progestin-only contraception: a meta-analysis 
Objectives To evaluate the risk of venous thromboembolic events associated with the use of progestin-only contraception and whether that risk differs with the mode of drug delivery (oral, intrauterine, or depot injection).
Design Systematic review and meta-analysis of randomised controlled trials and observational studies.
Data sources Pubmed, Embase, Cochrane Library, and reference lists of relevant reviews.
Study selection Randomised controlled trials and case-control, cohort, and cross sectional studies with venous thromboembolic outcome for progestin-only contraception reported relative to a non-hormone comparator group.
Data extraction Data were extracted by two independent investigators, and consensus for inclusion was reached after assessment by additional investigators.
Results Among the 2022 unique references identified by all searches, eight observational studies fulfilled inclusion criteria. A total of 147 women across all studies were diagnosed with a venous thromboembolic event while taking progestin-only contraception, and the summary measure for the adjusted relative risk of a venous thromboembolic episode for users versus non-users of a progestin-only contraceptive was, based on the random effects model, 1.03 (95% CI 0.76 to 1.39). Subgroup analysis confirmed there was no association between venous thromboembolic risk and progestin-only pills (relative risk 0.90 (0.57 to 1.45)) or a progestin intrauterine device (0.61 (0.24 to 1.53)). The relative risk of a venous thromboembolic event for users of an injectable progestin versus non-users was 2.67 (1.29 to 5.53).
Conclusions Published data assessing the risk of venous thromboembolism in women prescribed progestin-only contraception are limited. In this meta-analysis of eight observational studies, the use of progestin-only contraception was not associated with an increased risk of venous thromboembolism compared with non-users of hormonal contraception. The potential association between injectable progestins and thrombosis requires further study.
PMCID: PMC3413580  PMID: 22872710
24.  Effects of 17-α ethynyl estradiol on proliferation, differentiation & mineralization of osteoprecursor cells 
Background & objectives:
The steroidal estrogen 17α-ethynyl estradiol (EE) is an orally bio-active estrogen used in almost all modern formulations of estrogen-progestin combination preparations of oral contraceptives. Contrasting effects of treatment with combined oral contraceptives on bone mineral density of pre-, peri-, and post-menopausal women have been reported, and it has been suggested that the estrogen dose and the type of progestogen may be the main contributing factors for these contrasting results. The objective of this study was to evaluate the effects of EE on osteoprecursor cells.
The effects of single component of oral contraceptive, EE, were tested to see the relationship between EE and osteoblast proliferation, differentiation and mineralization. Tests used included a cell viability test, alkaline phosphatase (ALP) test, alizarin red-S staining, and a Western blot analysis. The effect on cell viability was determined by MTT assay. Differentiation and mineralization were examined using an ALP test and alizarin red-S staining. Protein expressions related to bone formation, such as estrogen receptor-alpha (ER-α), estrogen receptor-beta (ER-β), bone morphogenetic protein-2 (BMP-2), osteocalcin (OCN), and osteopontin (OPN) were evaluated by using a Western blot analysis.
Cultures growing in the absence of EE presented the lowest value for the MTT value. However, there were no significant changes in viability/proliferation when EE was added in the medium. Cultures growing in the absence of EE presented the highest value for the ALP activity, and the additional presence of EE resulted in dose-dependent decrease concerning ALP activity.
Interpretation & conclusions:
Our finding showed that EE in tested dosage within MC3T3-E1 cells seem to affect the proliferation and differentiation; however, significant differences are achieved in ALP activity in early differentiation phase and further studies are needed to elucidate the mechanisms of EE on bone.
PMCID: PMC3510894  PMID: 23041741
17-α ethynyl estradiol; differentiation; mineralization; osteoblast; proliferation
25.  Gallbladder selection for histopathological analysis based on a simple method: a prospective comparative study 
After a cholecystectomy, the current and traditional practice is to send each resected gallbladder to the pathologist for analysis. Some reports have suggested the possibility of selecting only those gallbladders that need to be analysed. The purpose of this study was to show a simple method for selecting which gallbladders should be sent to the pathologist.
A prospective comparative study was carried out. Two ‘tests’ were performed in 150 patients to detect or rule out gallbladder cancer. The first test included the patient's variables and a macroscopic gallbladder analysis performed by the surgeon (MGAS). The second test was the analysis performed by the pathologist. The results were compared.
Of the 150 patients, 132 were women and 18 men; 130 were under 60 years old. One patient had inflammatory bowel disease, seven had changes on ultrasonography and in four cases intra-operative disturbances were observed. During the MGAS, disturbances were found in 30 patients. Eighty-one cases (54%) had at least one or more risk factors for gallbladder cancer.
In almost half of the gallbladders, it would be safe not to send the specimen to the pathology department, decreasing costs significantly.
PMCID: PMC3705227  PMID: 22507718
Gallbladder; Adenocarcinoma; Cholecystectomy; Pathology; Diagnosis

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