Estrogen-containing Contraceptives Research Articles

Emphysema and a Hilar Mass in a Young Woman

SESSION TITLE: Imaging SESSION TYPE: Affiliate Case Report Poster PRESENTED ON: Tuesday, October 31, 2017 at 01:30 PM - 02:30 PM INTRODUCTION: Bronchial atresia is a congenital anomaly affecting the structure of the bronchial tree, wherein a disruption occurs in the bronchus following its formation. This disorder is often asymptomatic and diagnosed incidentally on chest imaging. CASE PRESENTATION: A 22-year old female non-smoker presented for evaluation of dyspnea on exertion and “congenital emphysema.” This finding was first noted incidentally two years prior when she was diagnosed with bilateral pulmonary emboli, secondary to the use of estrogen-containing contraception. Her medical history was otherwise unremarkable. She reported mild dyspnea on exertion and intermittent pleuritic chest pain. Vital signs were within normal limits, notable for oxygen saturation of 99% on room air. On physical examination, lung sounds were clear to auscultation, without audible wheezes or crackles with normal respiratory effort. No clubbing was present. Remainder of exam was unremarkable. Alpha-1-antitrypsin level was within normal limits (185 mg/dL). Pulmonary function tests (PFTs) were also normal. A CT chest demonstrated emphysematous changes in the right upper lobe, with a soft tissue density measuring 3.3x1.5 cm at the right superior hilum, consistent with a bronchocele. Further examination of the bronchial tree demonstrated atresia of the apical and posterior segments of the right upper lobe (Figure 1). DISCUSSION: Bronchial atresia is a condition of structural disruption in the bronchial tree. This anatomic anomaly is thought to be due to an insult, likely ischemic, during embryonic development in which the cells at the tip of the bronchial bud are disrupted from the bud itself. The distal bronchial tree forms normally, despite lack of communication to the proximal bronchus. The classic appearance on CT includes focal emphysema distal to the non-communicating airway, and a mucocele immediately distal to the site of atresia near the hilum. Aeration of the distal alveoli is theorized to result from collateral air-flow through intraalveolar pores of Kohn and bronchoalveolar channels of Lambert. Due to lack of communication with the proximal airway, air trapping occurs resulting in the appearance of emphysema. The distal bronchi function normally, causing mucus plugging at the atretic bronchus. Patients are generally asymptomatic, and this condition is most often discovered incidentally in adolescence. Treatment is usually not necessary; rarely surgery is indicated for recurrent infections. Most cases involve the left upper lobe, but cases at the right upper and middle lobe subsegments have been reported as well. CONCLUSIONS: Our patient presented with CT findings characteristic for bronchial atresia, with focal emphysema in the apicoposterior segments of the right upper lobe and mucocele distal to the atretic bronchus. Her pleuritic pain is felt to be related to the bulla abutting the pleura, and is treated with albuterol as needed. Reference #1: Gipson et al. Bronchial atresia. Radiographics 2009; 29:1531-5. DISCLOSURE: The following authors have nothing to disclose: Sarah Williams, Bethany Weiler-Lisowski, Avelino Verceles, Peter Bergquist No Product/Research Disclosure Information

The Influence of Hormonal Contraception on Vitamin D Supplementation on Serum 25(OH)D3 Status in Premenopausal Women: A Prospective Double-Blind Placebo Random Controlled Trial

Background: A number of cross-sectional studies have highlighted a potential benefit of estrogen-containing contraception on serum 25-hydroxyvitamin D (25(OH)D) levels. The purpose of the present prospective study was to determine whether oral vitamin D 3 supplementation significantly increases serum 25(OH)D more for women taking the estrogen-containing oral contraception than those not taking this medication. Methods: Thirty-eight premenopausal adult females aged 18 - 45 years old were recruited from a university campus; exclusion criteria included those presently taking vitamin D supplementation, those who stopped or started taking oral contraception in last 6 months and those taking any other form of contraception. A prospective double-blind placebo design was implemented; the dependent variable was serum 25(OH)D and the independent variables were using or not using oral estrogen-containing contraception, and vitamin D 3 or placebo supplementation. Participants were tested 4 weeks apart, and blood samples were collected using a capillary blood spot sample method and analyzed by liquid chromatography-tandem mass spectrometry. An independent technician prepared the identical supplement bottles with either 100 placebo pills or 100 active vitamin D 3 pills (1,000 IU per pill) and participants randomly selected a supplement bottle. Results: Baseline measurements of 25(OH)D were non-significantly 11% higher in those taking estrogen. ANOVA results revealed a significant two-way interaction between supplementation group (treatment vs. placebo) and treatment period (before vs. after) (P < 0.001), demonstrating a substantial rise in serum 25(OH)D for the treatment group compared with the placebo group. The results also identified a three-way interaction (P = 0.014) on serum 25(OH)D between the three independent variables, with the vitamin D oral contraception group having significantly greater serum 25(OH)D increases (from 45.9 to 98.3 nmol/L) compared with those not taking oral contraception (44.2 - 69.6 nmol/L) (P = 0.019). Conclusions: The estrogen-containing oral contraception increases serum 25(OH)D in premenopausal women with a magnified effect in those taking vitamin D supplementation. Future studies need to examine the relationship between estrogen, vitamin D supplementation, serum 25(OH)D, 1,25(OH)D, parathyroid hormone and other markers of bone metabolisms. J Endocrinol Metab. 2017;7(4):117-121 doi: https://doi.org/10.14740/jem441w

Effectiveness of the progestin-only pill for migraine treatment in women: A systematic review and meta-analysis.

Background Migraine is highly prevalent in women (18%). Peak morbidity affects their most productive years, coinciding with peak fertility. Hormonal contraception is often tailored for migraine prevention. Estrogen-containing contraceptives may be contraindicated in women experiencing migraine with aura due to the risk of vascular events. While improvements in migraine with a progestin-only pill (POP), which inhibits ovulation are documented, the strength and quality of evidence has not been formally evaluated. Objectives To determine the effectiveness of progestin-only contraceptives for migraine treatment by systematic review and meta-analysis. Data sources and selection MEDLINE, EMBASE and Cochrane Libraries were searched (1980 to September 2016) for studies on progestin-only treatments for migraine. Studies in English on >4 non-menopausal women aged 18-50 with migraine diagnosed by formal criteria were included. Data extraction and analysis Data were quality-assessed using the GRADE system. A random effects model was used for pooled analyses. Results Pooled analyses of four studies demonstrated that desogestrel 75 mcg/day, POP significantly but modestly reduced the number of migraine attacks and migraine days. Reduced intensity and duration, reduced analgesic and triptan use were observed, along with improved headache-related quality of life. GRADE analysis indicated evidence was low to very low for each outcome measure. Adverse effects resulted in treatment cessation for <10% of participants. Two studies compared desogestrel POP to a combined oral contraceptive, demonstrating similar migraine outcomes for both treatments. Conclusions The desogestrel POP shows promise in improving migraine in women. Current evidence is observational and based on small samples of women using only one oral progestin-only formulation. Further randomized trials on additional progestin-only contraceptives are required to confirm their role in migraine management.

Contraception in Patients with Rheumatic Disease.

Contraception represents an important area of reproductive health for patients with rheumatic diseases given the potential pregnancy risks associated with active disease, teratogenic medications, and severe disease-related damage. A high proportion of patients with rheumatic disease do not use effective contraception. Long-acting contraceptives are most effective. Antiphospholipid-negative patients with stable systemic lupus erythematosus may use oral combined contraceptives. Antiphospholipid-positive patients, or patients with rheumatic disease with other risk factors for thrombosis, should avoid estrogen-containing contraceptives. Contraceptive methods should be addressed by both the rheumatologist and gynecologist to determine the safest, most effective, and most convenient form for each patient.

The Influence of Hormonal Contraception on Vitamin D Supplementation on Serum 25(OH)D3 Status in Premenopausal Women: A Prospective Double-Blind Placebo Random Controlled Trial

Background: A number of cross-sectional studies have highlighted a potential benefit of estrogen-containing contraception on serum 25-hydroxyvitamin D (25(OH)D) levels. The purpose of the present prospective study was to determine whether oral vitamin D 3 supplementation significantly increases serum 25(OH)D more for women taking the estrogen-containing oral contraception than those not taking this medication. Methods: Thirty-eight premenopausal adult females aged 18 - 45 years old were recruited from a university campus; exclusion criteria included those presently taking vitamin D supplementation, those who stopped or started taking oral contraception in last 6 months and those taking any other form of contraception. A prospective double-blind placebo design was implemented; the dependent variable was serum 25(OH)D and the independent variables were using or not using oral estrogen-containing contraception, and vitamin D 3 or placebo supplementation. Participants were tested 4 weeks apart, and blood samples were collected using a capillary blood spot sample method and analyzed by liquid chromatography-tandem mass spectrometry. An independent technician prepared the identical supplement bottles with either 100 placebo pills or 100 active vitamin D 3 pills (1,000 IU per pill) and participants randomly selected a supplement bottle. Results: Baseline measurements of 25(OH)D were non-significantly 11% higher in those taking estrogen. ANOVA results revealed a significant two-way interaction between supplementation group (treatment vs. placebo) and treatment period (before vs. after) (P &lt; 0.001), demonstrating a substantial rise in serum 25(OH)D for the treatment group compared with the placebo group. The results also identified a three-way interaction (P = 0.014) on serum 25(OH)D between the three independent variables, with the vitamin D oral contraception group having significantly greater serum 25(OH)D increases (from 45.9 to 98.3 nmol/L) compared with those not taking oral contraception (44.2 - 69.6 nmol/L) (P = 0.019). Conclusions: The estrogen-containing oral contraception increases serum 25(OH)D in premenopausal women with a magnified effect in those taking vitamin D supplementation. Future studies need to examine the relationship between estrogen, vitamin D supplementation, serum 25(OH)D, 1,25(OH)D, parathyroid hormone and other markers of bone metabolisms. J Endocrinol Metab. 2017;7(4):117-121 doi: https://doi.org/10.14740/jem441w

Use of Estrogen-Containing Contraception Is Associated With Increased Concentrations of 25-Hydroxy Vitamin D

Small studies suggest exogenous estrogen may improve vitamin D status, but the etiology is unclear because women who use hormones may make lifestyle choices that differentially affect vitamin D status. Our objective was to investigate the association between use of hormonal contraception and 25-hydroxy-vitamin D (25(OH)D). We used linear regression modeling of cross-sectional data to estimate percent change in season-adjusted serum 25(OH)D with estrogen use after adjustment for other factors. At the enrollment clinic visit (2010-2012) into a cohort study of uterine fibroids, each subject provided a blood sample, had anthropomorphic variables and skin reflectance measured, and answered questionnaires on demographics, dietary and supplement intake, contraceptive use, reproductive and medical history, and behaviors. A total of 1662 African American women, community volunteers, 23-34 years old, living in the Detroit, Michigan, area were included. None. Serum 25(OH)D was measured. Serum 25(OH)D concentrations were low (70% <20 ng/ml). Current use of an estrogen-containing contraceptive was associated with a 20% (95% confidence interval: 14-27) increase in 25(OH)D after adjustment. There was no increase in 25(OH)D among participants who had used estrogen in the past, but were not current users, indicating that results were unlikely to be due to unmeasured confounding by factors related to contraceptive choice. The increase in 25(OH)D with use of estrogen-containing contraceptives raise mechanistic questions regarding the biological pathways involved, and highlights the need for studies that examine possible endogenous estrogen effects on vitamin D.

Contraception: Efficacy, Risks, Continuation Rates, and Use in High-Risk Women.

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. In this clinical update, we selected recent publications relevant to the use of contraceptive methods. We highlight articles on continuation rates of long-acting reversible contraception versus nonlong-acting methods, updated risks of intrauterine devices, use of estrogen-containing contraceptives during anticoagulation for venous thromboembolic events, and the efficacy of oral and emergency contraception in women with elevated body mass index.

Combined hormonal contraception use in reproductive-age women with contraindications to estrogen use

The Centers for Disease Control and Prevention's US Medical Eligibility Criteria for Contraceptive Use recommends that combined hormonal contraceptives (ie, birth control pills, contraceptive patch, vaginal ring) should be avoided in women with specific medical conditions because of the increased risk of cardiovascular events associated with estrogen use. Whether women with category 3 (theoretical or proven risk usually outweigh the advantages) or category 4 (unacceptable health risk) contraindications are appropriately avoiding estrogen-containing combined hormonal contraceptives is unknown. We describe the prevalence of combined hormonal contraceptive use among a sample of reproductive-age women with medical contraindications to estrogen use. Our hypothesis was that women with categories 3 and 4 contraindications would use estrogen-containing contraception less often than women without medical contraindications. We also explored whether inappropriate estrogen-containing contraceptive use is related to contraceptive provider characteristics. Data are from the baseline survey of the MyNewOptions study, which included privately insured women residing in Pennsylvania aged 18-40 years, who were sexually active and not intending pregnancy in the next year. Women were surveyed about their medical conditions, contraceptive use, and characteristics of their contraceptive provider. Women were considered to have a contraindication to combined hormonal contraceptives if they reported a category 3 or category 4 contraindication: hypertension, smokers older than age 35 years, a history of venous thromboembolism, diabetes with complications, coronary artery disease, systemic lupus erythematosus with antiphospholipid antibodies, breast cancer, or migraine headaches with aura. χ(2) tests for general association were used to compare combined hormonal contraceptives use, contraceptive health provider characteristics, and sociodemographic data in women with and without contraindications to estrogen use. The MyNewOptions baseline study sample included 987 adult women who were mostly young (46% were 18-25 years), white (94%), employed (70%), and married or cohabiting (54%). Thirteen percent (n= 130) of the sample had a medical contraindication to estrogen-containing contraceptive use: migraine with aura (81%) was the most common contraindication, followed by smokers older than age 35 years (7%), hypertension (11%), history of venous thromboembolism (4%), and diabetes with complications (2%). High use of combined hormonal contraceptives was reported among the women with medical contraindications to estrogen at 39% (n= 51). This was not statistically different from women without a medical contraindication (47%, P= .1). Among the 130 women with a contraindication, whether they did or did not use an estrogen-containing contraceptive did not vary by education level, income, or weight category. With respect to their contraceptive prescribers, there were no differences in prescriber specialty, provider type, or clinic type comparing women using and not using an estrogen-containing contraceptive. Among this study sample of reproductive-age women, there was a high rate of combined hormonal contraceptive use in women with a medical contraindication to estrogen use. These women may be at an increased risk for cardiovascular events. Processes need to be improved to ensure that women with medical contraindications to estrogen-containing contraception are being offered the safest and most effective methods, including long-acting reversible contraceptives, such as intrauterine devices and the contraceptive implant.

Recurrent venous thromboembolism and abnormal uterine bleeding with anticoagulant and hormone therapy use

AbstractWomen receiving vitamin K antagonists (VKAs) require adequate contraception because of the potential for fetal complications. It is unknown whether the use of hormonal therapy, especially those containing estrogens, is associated with recurrent venous thromboembolism (VTE) during anticoagulation. Despite the absence of data, World Health Organization guidelines state that use of estrogen-containing contraceptives confers an “unacceptable health risk” during established anticoagulation for VTE. We compared the incidences of recurrent VTE and abnormal uterine bleeding with and without concomitant hormonal therapy in women aged <60 years who were receiving anticoagulation with rivaroxaban or enoxaparin/VKA for confirmed VTE. Incidence densities in percentage per year were computed for the on and off estrogen-containing or progestin-only therapy periods. Cox regression models were fitted, with hormonal therapy (on vs off) as a time-dependent variable to derive the hazard ratio (HR) for the effects on recurrent VTE and abnormal uterine bleeding. In total, 1888 women were included. VTE incidence densities on and off hormonal therapy were 3.7%/year and 4.7%/year (adjusted HR, 0.56; 95% confidence interval [CI], 0.23-1.39), respectively, and were 3.7%/year and 3.8%/year, respectively, for estrogen-containing and progestin-only therapy. The adjusted HR for all abnormal uterine bleeding (on vs off hormonal therapy) was 1.02 (95% CI, 0.66-1.57). Abnormal uterine bleeding occurred more frequently with rivaroxaban than with enoxaparin/VKA (HR, 2.13; 95% CI, 1.57-2.89). Hormonal therapy was not associated with an increased risk of recurrent VTE in women receiving therapeutic anticoagulation. The observed increased risk of abnormal uterine bleeding with rivaroxaban needs further exploration.

Contraception-Related Venous Thromboembolism in Adolescents

Venous thromboembolism (VTE) is a rare but serious complication of combined hormonal contraception. While the absolute risk of VTE is low in adolescents, thrombotic events in contraception users younger than the age of 20 years account for 5 to 10% of total contraception-related VTE events in population studies, because of the high frequency of contraception use in adolescents. An increased risk of VTE exists not only with oral contraceptives, but also the contraceptive patch and vaginal ring. Most adolescents who experience contraception-related VTE have additional transient or inherited thrombotic risk factors at the time of VTE. Although the presence of inherited thrombophilia impacts the risk of contraception-related VTE, thrombophilia screening before contraception prescribing should be targeted only to high-risk populations. Pediatric institutions, caregivers, and young women need to be aware of the risk of VTE with estrogen-containing contraception, and maintain a high index of suspicion for this complication in women using these agents.

Uterine cervical ectopy during reproductive age: Cytological and microbiological findings

Cervical ectopy is common in adolescents, pregnant women, and those taking high doses of estrogen-containing contraceptives. The majority of cases have spontaneous reversion, but some cases can be persistent. Studies suggested that the adequacy of a Pap smear could be affected and there is an increased risk cervical infections. This study is a cross-sectional study conducted from December 2009 to February 2011 with 457 women with cervical ectopy and 736 without ectopy. Cervical samples were collected in vials for analysis by ThinPrep cytology (Hologic, Marlborough, MA). The Mann-Whitney test and Fisher's exact test (95% CI) were applied. The study was approved by the ethics committee of the Federal University of Ceará. The mean ages of the study group and control group were 28.7 (±14.8) and 33.6 (±7.5) years old, respectively (P < 0.0001). Negative diagnosis for malignancy and intraepithelial lesion was present in 399 (87%) cases and 705 (96%) in the study and control groups, respectively (P < 0.0001). Shift in the flora suggestive of bacterial vaginosis (BV) was observed more frequently in the study group: 74 (16.2%) than in the control group: 86(11.7%) (P = 0.017). The differences among the other morphotypes showed no significance. The smears were atypical in 12.7% (58/457) of the patients from the study group and in 4.2% (31/736) in the control group (P < 0.001; RR = 3 [2.033-4.712]). The association between ectopy and inflammatory cytology, the presence of the shift in the flora suggestive of BV and cytological atypia is evident.

Menstrual Disorders

Menstrual Disorders

Race, gender, and nicotine metabolism in adolescent smokers.

Differences in the rate of nicotine metabolism between genders and different races have been hypothesized to contribute to disparities in smoking rate, susceptibility to addiction, and ability to quit smoking. The purpose of this study was to determine the effect of race and gender on the rate of nicotine metabolism as indicated by the nicotine metabolite ratio (NMR) in adolescent smokers. One hundred and fifty-nine adolescent smokers aged 13-17 were given 2mg of deuterium-labeled cotinine (cotinine-d4). The NMR was calculated as the ratio of concentrations of deuterium-labeled 3'-hydroxycotinine (ng/ml) to cotinine-d4 (ng/ml) in saliva and is a validated biomarker of the rate of nicotine metabolism. The sample was 67.3% female and racially mixed. On average, Whites had the fastest rates of metabolism compared with both Blacks/African Americans (p < .01) and Asians (p = .01). The NMR was similar between males and females (p = .70). Among the 19 girls who reported using estrogen-containing contraceptives, there was no significant difference in NMR compared with the 83 girls who did not use contraceptives (p = .24) or the 10 who used progestin-only contraceptives (p = .45). Among adolescent smokers, racial variations in rates of nicotine metabolism were similar to those that have been reported in adult smokers. In contrast to findings in adult smokers, the NMR did not vary significantly by gender or self-reported hormone use.

Recurrence of Bacterial Vaginosis Is Significantly Associated With Posttreatment Sexual Activities and Hormonal Contraceptive Use

Bacterial vaginosis (BV) recurrence posttreatment is common. Our aim was to determine if behaviors were associated with BV recurrence in women in a randomized controlled trial (RCT). Symptomatic 18- to 50-year-old females with BV (≥3 Amsel criteria and Nugent score [NS] = 4-10) were enrolled in a 3-arm randomized double-blind RCT Melbourne Sexual Health Centre, Australia, in 2009-2010. All 450 participants received oral metronidazole (7 days) and were equally randomized to vaginal clindamycin, lactobacillus-vaginal probiotic or vaginal placebo. At 1, 2, 3, and 6 months, participants self-collected vaginal smears and completed questionnaires. Primary endpoint was NS = 7-10. Cox regression was used to estimate hazard ratios (HRs) for risk of BV recurrence associated with baseline and longitudinal characteristics. Four hundred four (90%) women with postrandomization data contributed to analyses. Cumulative 6-month BV recurrence was 28% (95% confidence interval [CI], 24%-33%) and not associated with treatment. After stratifying for treatment and adjusting for age and sex frequency, recurrence was associated with having the same pre-/posttreatment sexual partner (adjusted HR [AHR] = 1.9; 95% CI, 1.2-3.0), inconsistent condom use (AHR = 1.9; 95% CI, 1.0-3.3), and being non-Australian (AHR = 1.5; 95% CI, 1.0-2.1), and halved with use of an estrogen-containing contraceptive (AHR = 0.5; 95% CI, .3-.8). Risk of BV recurrence was increased with the same pre-/posttreatment sexual partner and inconsistent condom use, and halved with use of estrogen-containing contraceptives. Behavioral and contraceptive practices may modify the effectiveness of BV treatment. ACTRN12607000350426.

Contraceptive counseling and use among women with systemic lupus erythematosus: A gap in health care quality?

Disease activity and medication use can complicate pregnancies in patients with systemic lupus erythematosus (SLE). We therefore examined contraceptive counseling and use among women in the University of California, San Francisco Lupus Outcomes Study. In 2008, we queried participants regarding their pregnancy intentions, contraceptive use, and receipt of contraceptive counseling. Premenopausal women age <45 years who were sexually active with men were considered at risk of pregnancy. We compared self-reported rates of contraceptive counseling and use stratified by treatment with teratogenic medications and by history of thrombosis or antiphospholipid antibodies (aPL), using chi-square tests. We used logistic regression models to examine predictors of contraceptive counseling and use. Among 206 women, 86 were at risk for unplanned pregnancy. Most (59%) had not received contraceptive counseling in the last year, 22% reported inconsistent contraceptive use, and 53% depended solely on barrier methods. Intrauterine device contraceptives (IUDs) were used by 13%. Women using potentially teratogenic medications were no more likely to have received contraceptive counseling, to have used contraception consistently, or to have used more effective contraceptives. A history of thrombosis or aPL did not account for low rates of hormonal methods. Four women with a history of thrombosis or aPL were using estrogen-containing contraceptives. Most women at risk for unplanned pregnancy reported no contraceptive counseling in the past year, despite common use of potentially teratogenic medications. Many relied upon contraceptive methods with high failure rates; few used IUDs. Some were inappropriately using estrogen-containing contraceptives. These findings suggest the need to improve the provision of contraceptive services to women with SLE.

Strategies to prevent unintended pregnancy: increasing use of long-acting reversible contraception

Despite increasing contraceptive availability, unintended pregnancy remains a global problem, representing as many as 30% of all known pregnancies. Various strategies have been proposed to reverse this disturbing trend, especially increased use of long-acting reversible contraceptive (LARC) methods. In this review we aim to discuss the role of LARC methods and importance of contraceptive counseling in reducing unintended pregnancy rates. References/resources cited were identified based on searches of medical literature (MEDLINE, 1990-2009), bibliographies of relevant publications and the Internet. LARC methods-copper intrauterine devices (IUDs), progestogen-releasing intrauterine system and injectable and implantable contraceptives-are safe and effective contraceptive options (unintended pregnancy rates with typical versus perfect use: 0.05-3.0 versus 0.05-0.6%) that are appropriate for a wide range of women seeking to limit or space childbearing. Despite their safety and efficacy records, these methods remain underutilized; injectable and implantable methods are used by an estimated 3.4% and intrauterine methods by 15.5% of women worldwide. LARC methods require no daily or coital adherence and avoid the adverse events and health risks of estrogen-containing contraceptives. The copper IUD and progestin-only injections and implants have been shown to be more cost-effective than more commonly used methods, such as condoms and the pill (5-year savings: $13,373-$14,122, LARC; $12,239, condoms; $12,879, pill). Women who are considering use of LARC methods should receive comprehensive contraceptive counseling, as women who receive counseling before use demonstrate higher rates of after-use method satisfaction, continuation and acceptance than those who do not.

Safety and tolerability of frovatriptan in the acute treatment of migraine and prevention of menstrual migraine: Results of a new analysis of data from five previously published studies

Triptans are a recommended first-line treatment for moderate to severe migraine. Using clinical trial data, we evaluated the safety and tolerability of frovatriptan as acute treatment (AT) and as short-term preventive (STP) therapy for menstrual migraine (MM). Data from 2 Phase III AT trials (AT1: randomized, placebo controlled, 1 attack; AT2: 12-months, noncomparative, open label) and 3 Phase IIIb STP trials in MM (MMP1 and MMP2: randomized, placebo controlled, double blind, 3 perimenstrual periods; MMP3: open label, noncomparative, 12 perimenstrual periods) were analyzed. In AT1, patients treated each attack with frovatriptan 2.5 mg, sumatriptan 100 mg, or placebo. In AT2, they used frovatriptan 2.5 mg. In MMP1 and MMP2, women administered frovatriptan 2.5 mg for 6 days during the perimenstrual period, taking a loading dose of 2 or 4 tablets on day 1, followed by once-daily or BID frovatriptan 2.5 mg, respectively; in MMP3, they used BID frovatriptan 2.5 mg. In AT1, which was previously published in part, group differences in adverse events (AEs) were analyzed using the Fisher exact test, and response rates were compared using logistic regression. Post hoc analyses of sustained pain-free status with no AEs (SNAE) and sustained pain response with no AEs (SPRNAE) were performed using a 2-sample test for equality of proportions without continuity correction. For AT2 and the STP studies, data were summarized using descriptive statistics. Results of individual safety analyses for the STP studies were previously reported; the present report includes new results from a pooled analysis of MMP1 and MMP2 and a new analysis of MMP3 in which AEs were coded using Medical Dictionary for Regulatory Activities version 8.0. AT1 included 1206 patients in the safety group; AT2 included 496. In the STP studies, safety data were collected for 1487 women. In AT1 and AT2, 85.6% and 88.3%, respectively, of enrolled patients were women. Overall, AEs were generally mild to moderate (AT studies: 82.3%-90.0%; STP studies: 78.9%89.5%). In AT1, 27.3% (131/480) of frovatriptan patients, 33.4% (161/482) of sumatriptan patients, and 14.8% (36/244) of placebo patients experienced an AE considered possibly or probably related to treatment (P < 0.001 for either drug vs placebo).There were no significant differences between frovatriptan and sumatriptan in SNAE at 4 to 24 hours or in SPRNAE at 2 to 24 hours or at 4 to 24 hours. In randomized, controlled STP trials for MM, AEs were reported by 57.8% (166/287, BID) and 63.4% (210/331, once daily) of frovatriptan users versus 62.8% (216/344) of placebo recipients. There were no consistent differences in AEs reported by patients with potential cardiovascular risk or in AEs related to the use of estrogencontaining contraceptives (ECCs). In randomized controlled trials and 12-month open-label studies, frovatriptan was well tolerated in these women during AT and STP therapy for MM. Subgroup analyses provide preliminary evidence of tolerability in women using ECCs and in women with comorbidities that do not contraindicate triptan use but may be suggestive of cardiovascular risk.

Contraceptive Implants

Implantable contraception has been extensively used worldwide. Implants are one of the most effective and reversible methods of contraception available. These devices may be particularly appropriate for certain populations of women, including women who cannot use estrogen-containing contraception. Implants are safe for use by women with many chronic medical problems. The newest implant, Implanon (Organon International, Oss, The Netherlands), is the only device currently available in the United States and was approved in 2006. It is registered for 3 years of pregnancy prevention. Contraceptive implants have failure rates similar to tubal ligation, and yet they are readily reversible with a return to fertility within days of removal. Moreover, these contraceptive devices can be safely placed in the immediate postpartum period, ensuring good contraceptive coverage for women who may be at risk for an unintended pregnancy. Irregular bleeding is a common side effect for all progestin-only contraceptive implants. Preinsertion counseling should address possible side effects, and treatment may be offered to women who experience prolonged or frequent bleeding.

Pharmacokinetics of Two 6-Day Frovatriptan Dosing Regimens Used for the Short-Term Prevention of Menstrual Migraine

This study aimed to assess the pharmacokinetics and tolerability of once- and twice-daily frovatriptan given for 6 days, a regimen that has previously been reported to reduce the incidence and severity of menstrual migraine when administered during the perimenstrual period. This was a double-blind, placebo-controlled, two-period crossover study carried out in healthy premenopausal female volunteers aged >or=18 years (equal number taking or not taking estrogen-containing contraceptives [ECCs]) who were admitted to a clinical pharmacology unit. Women alternately received frovatriptan once daily (day 1: 5 mg; days 2-6: 2.5 mg) and twice daily (day 1: 5 mg [10 mg total]; days 2-6: 2.5 mg [5 mg total]) in a randomized treatment sequence. Dosing was also random with respect to the menstrual cycle. Whole blood samples were obtained on days 1 and 6 (predose and at 0.5, 1, 2, 4, 6, 8, 12 [before evening dose], 13, 14, 16 and 18 hours post-dose) and on days 2-5 (samples were taken before the morning dose). A final sample was drawn at 24 hours after the last treatment on day 6. A fully validated liquid chromatography assay coupled to a tandem mass spectroscopy assay measured drug concentrations (simultaneous measurement of frovatriptan and its metabolites). Pharmacokinetic parameters were determined using a noncompartmental approach. Safety and tolerability were measured by monitoring adverse events, haematology and biochemistry, vital signs, ECG results and physical examination findings. Twenty-six healthy women participated in the study and 24 (12 ECC users and 12 ECC nonusers) completed the study. One ECC user during period 1 and one nonuser during period 2 withdrew before completion; both were taking frovatriptan once daily. Most women were White (n = 21), three were Black, and one each was Hispanic or Asian; mean +/- SD age was 25.4 +/- 4.9 years; and mean +/- SD weight was 61.9 +/- 6.5 kg. For both once- and twice-daily dosing, time to reach maximum blood concentration (C(max)) [t(max)] was in the range of 2-4 hours. The loading dose enabled steady state (defined as constant trough blood concentration [C(min)]) to be reached by day 2 with both regimens. Geometric mean C(max) and area under the blood concentration-time curve from 0 to 12 hours (AUC(12)) were higher with twice- versus once-daily dosing (day 1: p < 0.02; day 6: p < 0.001 for both). C(min) was lower with once- (range 0.8-1.7 ng/mL) versus twice-daily frovatriptan (range 1.7-3.6 ng/mL). The ratio of C(max) : C(min) on days 1 and 6 was lower with twice- than with once-daily dosing, indicating less fluctuation in frovatriptan blood concentrations. ECC users had 26-68% higher C(max) and AUC from 0 to 24 hours values than nonusers on days 1 and 6 (p < 0.02); the clinical relevance of this is not known. Both dosing regimens were well tolerated; one incident of vomiting and one of headache were rated as moderate, with all other adverse events being rated as mild. Both frovatriptan regimens achieved steady-state therapeutic blood concentrations by day 2. Twice-daily dosing maintained more consistent drug concentrations than once-daily dosing and was well tolerated.

Review of the safety, efficacy and patient acceptability of the levonorgestrel-releasing intrauterine system.

The levonorgestrel-containing intrauterine system is an extremely effective, reversible and safe form of long-term yet reversible birth control. In view of its efficacy, it is a safer alternative to permanent contraceptive methods such as sterilization. It is especially useful in situations where use of estrogen-containing contraceptives is contraindicated. While menstrual disturbances are a common side effect, proper counseling improves compliance. In addition to its contraceptive effect, the levonorgestrel intrauterine system offers potential therapeutic benefits in other clinical contexts, including menorrhagia, symptomatic fibroids, endometriosis, and endometrial protection.