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.
drospirenone; premenstrual dysphoric disorder; acne vulgaris; contraception; antimineralocorticoid activity; antiandrogenic activity
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.
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.
drospirenone; premenstrual dysphoric disorder; premenstrual syndrome; oral contraceptive pill
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.
Ethinyl estradiol (EE) increases endothelium-dependent vasodilation in young women, but certain progestins paired with EE in combination OCPs have been shown to antagonize the vasodilatory effects of EE. Therefore, the purpose of this study was to investigate how endothelial function, serum biomarkers, and resting blood pressures change across an OCP cycle in women using a monophasic OCP formulation containing the progestin drospirenone.
Twelve women were studied during two hormone phases of their OCP cycle; once at the end of three weeks of active pills (30 mcg EE and 3.0 mg drospirenone), and once at the end of a week of placebo pills (no exogenous hormones).
Endothelium-dependent vasodilation was greater during the active phase compared to the placebo phase (p < 0.001). In contrast, there was no difference in endothelium-independent dilation between hormone phases.
These data suggest that the combination of 30 mcg EE and 3.0 mg drospirenone used in the active phase of this OCP increases endothelium-dependent vasodilation compared to a placebo phase.
progestin; estrogen; vasodilation; birth control pills; drospirenone; blood pressure
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.
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.
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.
oral contraceptive pills; progestins; vascular endothelium; iron
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.
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.
NuvaRing®; Oral Contraception; Ovarian Suppression
The primary objective was to assess the efficacy, cycle control and tolerability of a monophasic combined oral contraceptive (COC) containing nomegestrol acetate (NOMAC) and 17β-oestradiol (E2). Effects on acne were evaluated as a secondary objective. Results were compared to those of a COC containing drospirenone (DRSP) and ethinylestradiol (EE).
Women (aged 18-50 years) were randomised to receive NOMAC/E2 (2.5 mg/1.5 mg) in a 24/4-day regimen (n = 1591) or DRSP/EE (3 mg/30 μg) in a 21/7-day regimen (n = 535) for 13 cycles.
Estimated Pearl Indices for NOMAC/E2 and DRSP/EE were 0.38 and 0.81 in women aged ≤ 35 years and 0.31 and 0.66 for all women (18–50 years), respectively. Scheduled withdrawal bleedings were shorter and lighter among users of NOMAC/E2 and were sometimes absent altogether. Intracyclic bleeding/spotting was infrequent in both groups, and decreased over time. Type and frequency of adverse events were similar to those typically reported for COCs.
These data show that NOMAC/E2 provides high contraceptive efficacy with acceptable cycle control as well as an overall adverse event profile similar to that of DRSP/EE.
Combined oral contraceptive; Nomegestrol acetate; 17β-oestradiol; Efficacy; Safety; Cycle control
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.
oral contraception; nomegestrol acetate; estradiol
OBJECTIVE: To determine the influence of oral contraceptives (particularly those containing modern progestins) on the risk for ischaemic stroke in women aged 16-44 years. DESIGN: Matched case-control study. SETTING: 16 Centres in the United Kingdom, Germany, France, Switzerland, and Austria. SUBJECTS: Cases were 220 women aged 16-44 who had an incident ischaemic stroke. Controls were 775 women (at least one hospital and one community control per case) unaffected by stroke who were matched with the corresponding case for 5 year age band and for hospital or community setting. Information on exposure and confounding variables were collected in a face to face interview. MAIN OUTCOME MEASURES: Odds ratios derived with stratified analysis and unconditional logistic regression to adjust for potential confounding. RESULTS: Adjusted odds ratios (95% confidence intervals) for ischaemic stroke (unmatched analysis) were 4.4 (2.0 to 9.9), 3.4 (2.1 to 5.5), and 3.9 (2.3 to 6.6) for current use of first, second, and third generation oral contraceptives, respectively. The risk ratio for third versus second generation was 1.1 (0.7 to 2.0) and was similar in the United Kingdom and other European countries. The risk estimates were lower if blood pressure was checked before prescription. CONCLUSION: Although there is a small relative risk of occlusive stroke for women of reproductive age who currently use oral contraceptives, the attributable risk is very small because the incidence in this age range is very low. There is no difference between the risk of oral contraceptives of the third and second generation; only first generation oral contraceptives seem to be associated with a higher risk. This small increase in risk may be further reduced by efforts to control cardiovascular risk factors, particularly high blood pressure.
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.
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.
Most combination oral contraceptives contain ethinyl estradiol and a progestin. A new and novel oral contraceptive formulation combines estradiol valerate (E2V) with dienogest (DNG) in a four-phase dosing regimen. 17β-estradiol is a naturally-occurring estrogen, and a contraceptive pill containing such an estrogen offers potential benefits with regard to metabolic side effects and adverse events. Dienogest is derived from 19-nortestosterone and exerts profound progestational effects on the endometrium, but it differs from other progestins in its class by its antiandrogenic activity. Estradiol valerate plus dienogest (E2V/DNG) is now available in a four-phasic regimen that integrates an estrogen stepdown and progestin stepup dosing approach along with a short two-day hormone-free interval. This regimen offers safe, reliable contraception and has been shown to be an effective treatment for heavy menstrual bleeding. Metabolic effects and adverse events appear similar to those reported with oral contraceptives containing ethinyl estradiol.
estradiol valerate; dienogest; oral contraception; combination
We examined oral contraceptive (OC) and menopausal hormonal therapy (MHT) use in relation to risk of B-cell non-Hodgkin lymphoma (NHL). Women under age 85 years participating in the California Teachers Study with no history of hematopoietic cancer were followed from 1995 through 2007. 516 of 114,131 women eligible for OC use analysis and 402 of 54,758 postmenopausal women eligible for MHT use analysis developed B-cell NHL. Multivariable adjusted and stratified Cox proportional hazards models were fit to estimate relative risks (RR) and 95% confidence intervals (95% CI). Ever versus never OC use was marginally associated with lower B-cell NHL risk, particularly among women first using OCs before age 25 years (RR=0.72, 95%CI=0.51-0.99); yet, no duration-response effect was observed. No association was observed for ever versus never MHT use among postmenopausal women (RR=1.05, 95%CI=0.83-1.33) overall, or by formulation (estrogen alone, ET, or estrogen plus progestin, EPT). Among women with no MHT use, having bilateral oophorectomy plus hysterectomy was associated with greater B-cell NHL risk than having natural menopause (RR=3.15, 95%CI=1.62-6.13). Bilateral oophorectomy plus hysterectomy was not associated with risk among women who used ET or EPT. These results indicate that exogenous hormone use does not strongly influence B-cell NHL risk.
non-Hodgkin lymphoma; oral contraceptives; menopausal hormonal therapy; hysterectomy; bilateral oophorectomy
Objective. To compare the efficacy of low-dose COC containing desogestrel (DSG) with drospirenone (DRSP) in the changes of premenstrual symptoms. Methods. In an open-label randomized controlled trial, 90 women with premenstrual syndrome who required COC were randomly recruited and allocated equally to receive either 6 cycles of 20 micrograms ethinyl estradiol (EE)/150 micrograms DSG (DSG group) or 20 micrograms EE/3 mg DRSP (DRSP group) in 24/4 extended regimen. Analysis of covariance and repeated analysis of variance were used to determine the difference of mean Women's Health Assessment Questionnaire (WHAQ) scores changes between groups, within group, and in premenstrual, menstrual, and postmenstrual phases. Results. Baseline characteristics and WHAQ scores were comparable. At the ends of the 3rd and the 6th cycles, mean WHAQ scores of all the 3 phases in DRSP group showed significant reduction and were significantly lower than those in DSG group. DSG group showed significant reduction in both premenstrual and menstrual phases after the 6th cycle. Adverse effects were comparable in both groups. In conclusion, low-dose COC containing either DSG or DRSP reduced premenstrual symptoms, but the latter showed greater efficacy and earlier reduction.
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.
Opinions differ regarding the association between gallbladder disease and oral contraceptive (OCs). The objective of this paper is to quantify cholecystectomy rate among women initiating OCs.
Women under age 25 years were enrolled at four sites in a randomized trial evaluating initiation of OCs. Hospitalizations while enrolled were elicited during follow-up interviews, and medical records of women who underwent cholecystectomy were reviewed.
Eight of 757 women enrolled at University of Texas Southwestern Medical Center (UTSW) underwent cholecystectomy, a rate of 25.3/1000 woman-years (95% CI 8.1, 42.5). All eight were Mexican-American and postpartum when they initiated OCs. The expected rate is 4.2/1000 woman-years for US women aged 15–44.
Women enrolled at the UTSW site had an increased rate of cholecystectomy, and were more likely to be postpartum and Mexican-American than women enrolled at the other sites.
Oral contraceptives; Mexican-American; postpartum; cholecystectomy; cholelithiasis; gallstones
This study was conducted to compare oral contraceptive (OC) pharmacokinetics (PK) in normal weight (BMI 19.0-24.9) and obese (BMI 30.0-39.9) women.
During the third week of the third cycle of OC use, we admitted 15 normal weight and 15 obese women for collection of 12 venous specimens over 24 h. Using RIA techniques, we measured levels of ethinyl estradiol (EE) and levonorgestrel (LNG). During the same cycle, women underwent twice-weekly sonography to assess ovarian follicular development and blood draws to measure endogenous estradiol (E2) and progesterone levels.
Obese women had a lower area under the curve (AUC; 1077.2 pg*h/mL vs 1413.7 pg*h/mL) and lower maximum values (85.7 pg/mL vs 129.5 pg/mL) for EE than normal weight women (p = 0.04 and 0.01, respectively); EE trough levels were similar between BMI groups. The similar, but smaller, differences in their LNG levels for AUC and maximum values (Cmax) were not statistically significant. While peak values differed somewhat, the LNG trough levels were similar for obese and normal weight women (2.6 ng/mL and 2.5 ng/mL, respectively). Women with greater EE AUC had smaller follicular diameters (p = 0.05) and lower E2 levels (p = 0.04). While follicular diameters tended to be larger among obese women, these differences were not statistically significant.
OC hormone peak levels are lower among obese women compared to normal weight women, but their trough levels are similar. In this small study, the observed PK differences did not translate into more ovarian follicular activity among obese OC users.
This study was conducted to compare breast epithelial-cell proliferation and estrogen and progesterone receptor levels in women taking one of two oral contraceptives (OCs) containing the same dose of estrogen but different doses of the progestin norethindrone (NET).
Thirty-three women were randomly assigned 1:1 to one of two OCs with 35-mcg ethinylestradiol (EE2) but different doses of NET - 1 mg or 0.4 mg. At the end of the active pill phase of the third OC cycle, a breast biopsy was performed and the percentages of epithelial cells of the terminal duct lobular units were measured for Ki67 (MIB1), progesterone receptors A and B (PRA and PRB), and estrogen receptor α (ERα).
The biopsies from 27 women had sufficient epithelium for analysis. The percentage of cells positive for PRA, PRB, and ERα were approximately double with the lower progestin dose (PRA: p = 0.041; PRB: p = 0.030; ERα: p = 0.056). The Ki67 percentage was not reduced with the lower progestin dose (0.4-mg NET - 12.5% vs 1.0-mg NET - 7.8%).
The increase in PRA, PRB, and ERα positive cells with the 60% lower progestin dose OC appears likely to account for its failure to decrease breast-cell proliferation. This breast-cell proliferation result is contrary to that predicted from the results of lowering the medroxyprogesterone acetate dose in menopausal hormone therapy.
Breast epithelial cells; Combined oral contraceptives; Estrogen receptor; Progesterone receptor; Progestin dose; Proliferation markers
This study was conducted to determine whether increased body mass index (BMI) affects oral contraceptive (OC) pharmacokinetics and suppression of hypothalamic-pituitary-ovarian (HPO) axis activity.
Ovulatory reproductive-age women of normal (< 25 kg/m2; n = 10) and obese (> 30 kg/m2; n = 10) BMI received OCs for two cycles (prospective cohort). Subjects were admitted for two 48-h inpatient stays at the beginning and end of the hormone-free interval. Ethinyl estradiol (EE) and levonorgestrel (LNG) levels were evaluated during both inpatient stays. Gonadotropin pulsatility (FSH and LH) was measured during the second inpatient stay. Estradiol (E2) and progesterone (P) were measured daily during inpatient stays and twice per week in Cycle 2.
BMI was greater in the obese, compared to the normal BMI group [37.3 kg/m2 (SD 6.0) versus 21.9 kg/m2 (SD 1.6); p < 0.05]. The LNG half-life was significantly longer in the obese group (52.1 ± 29.4 h versus 25.6 ± 9.3 h, p < 0.05) which correlated with a lower maximum LNG concentration on Cycle 2, Day 1 [1.9 ng/mL (SD 0.5) versus 2.5 ng/mL (SD 0.7)] and a longer time to reach steady-state (10 versus 5 days), in obese women. There were no significant differences in volume of distribution between groups. LH pulse parameters did not differ statistically between groups but trended towards greater HPO activity in the obese group. Additionally, more obese (6/10 versus 3/10 normal BMI, p > 0.05) women exhibited E2 levels consistent with development of a dominant follicle, and P levels consistent with ovulation (2/10 versus 1/10) during Cycle 2.
Compared to women of normal BMI, obese women exhibit differences in OC pharmacokinetics that are associated with greater HPO activity.
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.
contraception; thrombosis; thrombophilia; hormone
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.
reproductive history; oral contraceptive use; ovarian cancer; cohort study
Although epidemiological evidence for the ability of combined oral contraception (OC) to reduce the risk of ovarian cancer is convincing, the biological mechanisms underlying this effect are largely unknown. We conducted the present study to determine if OC also influences ovarian carcinogenesis in a genetic mouse model and, if so, to investigate the mechanism underlying the protective effect. LSL-K-rasG12D/+PtenloxP/loxP mice were treated with ethinyl estradiol plus norethindrone, contraceptive hormones commonly used in combined OC, or norethindrone alone, or a gonadotropin-releasing hormone (GnRH) agonist. The combined OC had a 29% reduction in mean total tumor weight compared with placebo (epithelial tumor weight, −80%). Norethindrone alone reduced mean total tumor weight by 42% (epithelial tumor weight, −46%), and the GnRH agonist increased mean total tumor weight by 71% (epithelial tumor weight, +150%). Large variations in tumor size affected the P-values for these changes, which were not statistically significant. Nonetheless, the OC reductions are consistent with the epidemiologic data indicating a protective effect of OC. Matrix metalloproteinase 2 activity was decreased in association with OC, indicating that OC may affect ovarian carcinogenesis by decreasing proteolytic activity, an important early event in the pathogenesis of ovarian cancer. In contrast, OC increased invasion in a K-ras/Pten ovarian cancer cell line established from the mouse tumors, suggesting that OC hormones, particularly estrogen, may have a detrimental effect after the disease process is underway. Our study results support further investigation of OC effects and mechanisms for ovarian cancer prevention.
ovarian cancer; prevention; norethindrone; ethinyl estradiol; GnRH agonist; genetic mouse model; combined oral contraception