Assessment of the Effects of Abrocitinib on the Pharmacokinetics of Probe Substrates of Cytochrome P450 1A2, 2B6 and 2C19 Enzymes and Hormonal Oral Contraceptives in Healthy Individuals.

BACKGROUND AND OBJECTIVE: Abrocitinib is an oral small-molecule Janus kinase (JAK)-1 inhibitor approved for the treatment of moderate-to-severe atopic dermatitis. In vitro studies indicated that abrocitinib is a weak time-dependent inhibitor of cytochrome P450 (CYP) 2C19/3A and a weak inducer of CYP1A2/2B6/2C19/3A. To assess the potential effect of abrocitinib on concomitant medications, drug-drug interaction (DDI) studies were conducted for abrocitinib with sensitive probe substrates of these CYP enzymes. The impact of abrocitinib on hormonal oral contraceptives (ethinyl estradiol and levonorgestrel), as substrates of CYP3A and important concomitant medications for female patients, was also evaluated. METHODS: Three Phase 1 DDI studies were performed to assess the impact of abrocitinib 200 mg once daily (QD) on the probe substrates of: (1) 1A2 (caffeine), 2B6 (efavirenz) and 2C19 (omeprazole) in a cocktail study; (2) 3A (midazolam); and (3) 3A (oral contraceptives). RESULTS: After multiple doses of abrocitinib 200 mg QD, there is a lack of effect on the pharmacokinetics of midazolam, efavirenz and contraceptives. Abrocitinib increased the area under the concentration time curve from 0 to infinity (AUCinf) and the maximum concentration (Cmax) of omeprazole by approximately 189 and 134%, respectively. Abrocitinib increased the AUCinf of caffeine by 40% with lack of effect on Cmax. CONCLUSIONS: Based on the study results, abrocitinib is a moderate inhibitor of CYP2C19. Caution should be exercised when using abrocitinib concomitantly with narrow therapeutic index medicines that are primarily metabolized by CYP2C19 enzyme. Abrocitinib is a mild inhibitor of CYP1A2; however, the impact is not clinically relevant, and no general dose adjustment is recommended for CYP1A2 substrates. Abrocitinib does not inhibit CYP3A or induce CYP1A2/2B6/2C19/3A and does not affect the pharmacokinetics of contraceptives. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov registration IDs: NCT03647670, NCT05067439, NCT03662516.

Actualización en anovulatorios orales combinados (AOC) / Update on combined oral anovulatory (AOC)

INTRODUCCIÓN: La anticoncepción, es única entre las intervenciones médicas por sus beneficios potenciales en la salud de las mujeres. Usar métodos eficaces y seguros, reduce la mortalidad materna, da libertad, calidad de vida y mejora la salud y sobrevida de los niños. Prevenir embarazos no planeados es una prioridad para Salud Pública. Por tratarse de una medida preventiva y de uso masivo, deben seleccionarse las prácticas con el mejor balance riesgo/beneficio. Los Anovulatorios Orales combinados (AOC), son los más usados y conocidos en nuestro país. ANTICONCEPCIÓN CON AOC: Es la anticoncepción con píldoras orales que contienen etinil estradiol (EE) combinado con un progestágeno en diferentes formulaciones. Los progestágenos existentes son: norgestrel y levonorgestrel, Desogestrel, Norgestimato, Gestodeno, Drospirenona y los más recientes: Dienogest, Nomegestrol y norelgestromin. AOC DISPONIBLES EN ARGENTINA: La mayoría de las formulaciones contienen EE más levonorgestrel, EE más desogestrel, EE más gestodeno, EE más norgestimato y EE más drospirenona en preparados monofásicos (la misma dosis todos los comprimidos) y bifásicos, trifásicos y multifásicos. Actualmente han sido autorizados para su comercialización en nuestro país, nuevos AOC conteniendo estrógenos diferentes del EE. Los estrógenos usados son: de Estradiol y 17 beta estradiol junto a dos nuevos progestágenos el Dienogest y el nomegestrol. Su efectividad anticonceptiva está probada pero sus perfiles de seguridad no han sido establecidos aún con respecto al EE. RIESGOS PARA LA SALUD: Los riesgos severos para la salud de los AOC están representados por incremento de trombosis venosa profundas y trombosis arteriales. Existe un aumento pequeño del RR de cáncer de mama y cáncer de cuello uterino.4,5. El riego absoluto de trombosis es pequeño, pero es mucho menor en las no usuarias o en las usuarias de progestágenos solos. El riego de trombosis también está asociado al tipo de progestágeno usado, es claramente menor con Levonorgestrel y noretisterona que con cualquiera de los otros progestágenos. BENEFICIOS NO ANTICONCEPTIVOS PARA LA SALUD: Se asocian a reducción del riesgo de cáncer de endometrio y cáncer colorrectal y varios efectos beneficiosos no contraceptivos como: regulación del ciclo con patrones de sangrado menores y predecibles, disminución del dolor menstrual y efectos beneficiosos en el síndrome de ovario poliquístico y la endometriosis. CRITERIOS DE ELEGIBILIDAD: Son los criterios establecidos por La OMS para determinar quiénes pueden o no usar determinados métodos de contracepción según algunas características personales (edad, estado puerperal, etc.) o condiciones de salud. PROVISIÓN Y ACCESIBILIDAD: Los AOC con mejor relación riesgo/beneficio se encuentran en el Formulario Terapéutico Provincial de Neuquén y están disponibles en los centros de salud.

Drospirenone-Containing Oral Contraceptive Pills and the Risk of Venous Thromboembolism: An Assessment of Risk in First-Time Users and Restarters.

INTRODUCTION: The effects of drospirenone-containing combined oral contraceptives (COCs) on the risk of venous thromboembolism (VTE) remain controversial due to the challenge in distinguishing between first-time users and restarters, and their different underlying VTE risks, in healthcare databases. OBJECTIVES: The aim of this study was to describe the challenge of studying the risk of VTE among first-time users of drospirenone-containing COCs in a healthcare database and assess the risk among first-time users and restarters. METHODS: We used data from the Clinical Practice Research Datalink to construct two cohorts. The first-time user cohort included all women aged 16-45 years who received a first ever prescription of drospirenone- or levonorgestrel-containing COCs between May 2002 and March 2015. The restarter cohort included those who were restarting a COC after a period of non-use of ≥6 months. Cox proportional hazards models adjusted for high dimensional propensity scores were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: The final cohorts included 55,139 first-time users (3582 drospirenone and 51,557 levonorgestrel) and 162,959 restarters (23,191 drospirenone and 139,768 levonorgestrel). The adjusted HR of VTE associated with drospirenone versus levonorgestrel was 3.19 (95% CI 1.12-9.08) for first-time users and 1.96 (95% CI 1.12-3.41) for restarters. CONCLUSIONS: We found an elevated risk of VTE associated with drospirenone-containing COCs in comparison with levonorgestrel-containing COCs in both cohorts. While left truncation of healthcare databases is a concern for the identification of first-time users, the use of a more explicit cohort of restarters suggests a doubling of VTE risk with drospirenone-containing COCs.

Long-term medical management of endometriosis with dienogest and with a gonadotropin-releasing hormone agonist and add-back hormone therapy.

Endometriosis can recur after either surgical or medical therapy. Long-term medical therapy is implemented to treat symptoms or prevent recurrence. Dienogest and gonadotropin-releasing hormone (GnRH) analogues with hormone add-back therapy seem to be equally effective for long-term treatment of pain symptoms associated with endometriosis. There is insufficient evidence to support the superiority of one therapy over the other. However, add-back hormone therapy (HT) is recommended for patients using GnRH agonists. The treatment selection depends on therapeutic effectiveness, tolerability, drug cost, the physician's experience, and expected patient compliance.

Continuous Norethisterone Acetate versus Cyclical Drospirenone 3 mg/Ethinyl Estradiol 20 µg for the Management of Primary Dysmenorrhea in Young Adult Women.

STUDY OBJECTIVE: To evaluate the efficacy of continuous norethisterone acetate (NET-A), 5 mg (group N) vs cyclical combined oral contraceptive pill (COC) consisting of drospirenone 3 mg/ethinyl estradiol 20 µg pills (group P) in treating dysmenorrhea in young adult women. DESIGN, SETTING, AND PARTICIPANTS: This prospective, open-label, nonrandomized study included 38 Jordanian patients: 20 patients in group N and 18 patients in group P. INTERVENTIONS: Continuous NET-A 5 mg daily or cyclical COC. MAIN OUTCOME MEASURES: Pain scores, adverse effects, analgesic use, school absence, and cost. RESULTS: Thirty-eight patients used NET-A or COC for 6 months. All participants had almost the same starting levels of visual analogue scale (VAS) scores. Both drugs were similar in suppressing dysmenorrhea at the 3-month follow-up visit; VAS score mean (±SD) in group N and P were 1.30 ± 1.22 and 1.28 ± 0.83 (P = .22), respectively, and after 6 months, with mean VAS scores (±SD) of 1.30 ± 1.22 and 1.28 ± 0.83, respectively (P = .95). The cost of the treatment in the N group was much less than in the P group. Participants in the N group were less likely to use pain killers: 20% and 44% in the N and P groups, respectively (P = .006) in the first month and only 5% and 17% (P = .019) in the N and P groups, respectively, at the 3-month follow-up, and none of them used any analgesics at the 6-month follow-up. CONCLUSION: A continuous NET-A regimen is a well tolerated, effective, and inexpensive option for dysmenorrhea treatment and was as good as COC.

Risk-benefit assessment of the combined oral contraceptive pill in women with a family history of female cancer.

INTRODUCTION: Oral contraceptive pills (OCPs) are the most frequently used form of effective, reversible contraception among women of childbearing potential. In the average risk population, OCPs may offer a protective benefit against ovarian, endometrial and colorectal malignancies. In women at high risk for breast, ovarian, endometrial or colorectal malignancies, the risk-benefit profile is less well studied. AREAS COVERED: In this article, we review pertinent literature on the use of OCPs in patients with genetic susceptibilities due to mutations in BRCA1, BRCA2 or mismatch repair genes implicated in hereditary nonpolyposis colorectal cancer as well as those with a strong family history of malignancies associated with these syndromes. EXPERT OPINION: For women at high risk for ovarian, endometrial and/or colorectal malignancies due to genetic susceptibilities or a strong family history, the possibility of chemoprevention with OCPs may be an attractive option; however, the potential increase in breast cancer, although small, must be considered in clinical decision-making. The ultimate decision to use OCPs in a high-risk woman should be based on a consideration of her specific genetic risk, her age, her reproductive plans and her willingness to consider surgical prophylaxis options.

Comparison of rates of and charges from pregnancy complications in users of extended and cyclic combined oral contraceptive (COC) regimens: a brief report.

OBJECTIVE: To evaluate pregnancy complication rates and related charges in users of 84/7, 21/7 and 24/4 combined oral contraceptives (COCs). STUDY DESIGN: Data were obtained from the i3 InVision Data Mart™ retrospective claims database. Subjects were aged 15-40 years, first prescribed a COC between 1/1/2006 and 4/1/2011 and continuously insured for ≥1 year. 84/7 users were matched 1:1 to 21/7 and 24/4 users. RESULTS: Pregnancy-related complication rates and associated charges were significantly lower with 84/7 vs. 21/7 and 24/4 regimens. CONCLUSION: Preliminary data suggest 84/7 regimens may be associated with fewer pregnancy complications and lower related charges.

Knowledge of users of low-dose oral combined contraceptives about the method / Conhecimento de usuarias de anticoncepcional oral combinado de baixa dose sobre o metodo / El conocimiento de las usuarias sobre el metodo de anticonceptivos orales de dosis bajas combinados

OBJECTIVES: to identify the knowledge of users of combined oral contraceptive about correct use, side effects and complications; to verify the correlation between knowledge about the method with age, education, family income and time of use. METHOD: cross-sectional study performed in Fortaleza, Ceará, Brazil, from March to July 2010, with 294 women. Data were collected through interviews. RESULTS: 75% had substantial knowledge about the proper use and side effects and no knowledge about complications. The higher the educational level and family income, the higher the women's knowledge about the correct use of the method. Positive correlation suggests that women who used the method for longer knew more about its side effects. CONCLUSION: there are knowledge gaps about the method, which are influenced by socioeconomic variables and use time. .

OBJETIVOS: identificar o conhecimento de usuárias de anticoncepcional oral combinado sobre uso correto, efeitos colaterais e complicações relacionados a esse uso; verificar correlação entre o conhecimento sobre o método com idade, escolaridade, renda familiar mensal e tempo de uso. MÉTODO: estudo transversal, desenvolvido em Fortaleza, Ceará, Brasil, de março a julho de 2010, com 294 mulheres. Os dados foram coletados por meio de entrevista. RESULTADOS: setenta e cinco por cento apresentaram conhecimento substancial para o uso correto e efeitos colaterais e nenhum conhecimento para complicações. Quanto maior a escolaridade e a renda familiar maior o conhecimento das mulheres sobre o uso correto do método. Correlação positiva sugere que mulheres que usaram o método por mais tempo conheciam mais sobre seus efeitos colaterais. CONCLUSÃO: há lacunas no conhecimento sobre o método, sendo essas influenciadas por variáveis socioeconômicas e tempo de uso. .

OBJETIVOS: Identificar el conocimiento de las usuarias de anticonceptivos orales combinados sobre el uso correcto, los efectos secundarios y complicaciones, para verificar la correlación entre el conocimiento sobre el método con la edad, la educación, el ingreso familiar y el tiempo de uso. MÉTODO: Estudio transversal realizado en Fortaleza, Ceará, Brasil, de marzo a julio de 2010, con 294 mujeres. Los datos fueron recolectados a través de entrevistas. RESULTADOS: el 75% tenía un conocimiento considerable sobre el uso adecuado y efectos secundarios y ningún conocimiento acerca de las complicaciones. Cuanto mayor es el nivel educativo y el ingreso familiar, mayor conocimiento de las mujeres sobre el uso correcto del método. La correlación positiva sugiere que las mujeres que utilizaron el método para ya sabían más acerca de sus efectos secundarios. CONCLUSIÓN: Hay lagunas en los conocimientos sobre el método, que son influenciados por variables socioeconómicas y el tiempo de uso. .

Characteristics of scheduled bleeding manipulation with combined hormonal contraception in university students.

BACKGROUND: There is a lack of information concerning the decision factors and sources of information influencing women who purposefully deviate from the prescribed use of their combined hormone contraceptives to exert elective control of their scheduled bleeding. STUDY DESIGN: A self-administered email survey of scheduled bleeding practices and beliefs was distributed to 11,900 female students at the University of Oregon. Assessment of survey participant characteristics, scheduled bleeding manipulation features and attitudes and knowledge toward hormonal contraception was analyzed. RESULTS: Of 1719 respondents to the survey, 1374 (79.9%) reported using combined hormonal contraception currently or recently. Approximately 17% of these women altered their scheduled bleeding pattern by deviating from package instructions. Of these, 50% indicated they delayed or skipped their scheduled bleeding for convenience or personal choice. Within this group, 47% of women indicated they learned to modify their scheduled bleeding from health care professionals, while 30% indicated such knowledge was obtained from family or friends. Characteristics that decreased the likelihood of this practice included being of Asian race, use of hormonal contraceptive for bleeding cycle regulation, following a regular exercise program, and personal preference for a monthly cycle. CONCLUSIONS: The majority of university females who choose to modify their scheduled bleeding cycle with combined hormonal contraceptives do so for convenience rather than to avoid menstrual symptoms, and many learn from nonmedical sources. There is some disparity between the preferences of menstruation frequency and actual scheduled bleeding pattern behaviors, suggesting potential for improvement in patient education.

Ethinyl estradiol and 17ß-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment.

The need to seek improved combined oral contraceptive (COC) efficacy, with fewer health risks and better acceptability, has been ongoing since the introduction of COCs more than 50 years ago. New progestin formulations combined with lower doses of ethinyl estradiol (EE), the predominant estrogenic component of COCs, have reduced the incidence of venous thromboembolism and other negative outcomes of COC treatment. Previous attempts to use endogenous 17ß-estradiol (E2) instead of EE were limited primarily by poor cycle control. The recent introduction of E2-based formulations has renewed interest to determine if there are potential benefits of using E2 in COCs. These formulations have been shown to have similar efficacy and cycle control as EE-based COCs. This review provides a brief summary of the pharmacology of EE and E2, including metabolism, pharmacokinetics and pharmacodynamics, as well as adverse effects of these estrogens.

Co-administration of vismodegib with rosiglitazone or combined oral contraceptive in patients with locally advanced or metastatic solid tumors: a pharmacokinetic assessment of drug-drug interaction potential.

PURPOSE: Vismodegib, a first-in-class oral hedgehog pathway inhibitor, is an effective treatment for advanced basal cell carcinoma. Based on in vitro data, a clinical drug-drug interaction (DDI) assessment of cytochrome P450 (CYP) 2C8 was necessary; vismodegib's teratogenic potential warranted a DDI study with oral contraceptives (OCs). METHODS: This single-arm, open-label study included two cohorts of patients with locally advanced or metastatic solid malignancies [Cohort 1: rosiglitazone 4 mg (selective CYP2C8 probe); Cohort 2: OC (norethindrone 1 mg/ethinyl estradiol 35 µg; CYP3A4 substrate)]. On Day 1, patients received rosiglitazone or OC. On Days 2-7, patients received vismodegib 150 mg/day. On Day 8, patients received vismodegib plus rosiglitazone or OC. The effect of vismodegib on rosiglitazone and OC pharmacokinetic parameters (primary objective) was evaluated through pharmacokinetic sampling over a 24-h period (Days 1 and 8). RESULTS: The mean ± SD vismodegib steady-state plasma concentration (Day 8, N = 51) was 20.6 ± 9.72 µM (range 7.93-62.4 µM). Rosiglitazone AUC(0-inf) and C(max) were similar with concomitant vismodegib [≤8% change in geometric mean ratios (GMRs); N = 24]. Concomitant vismodegib with OC did not affect ethinyl estradiol AUC(0-inf) and C(max) (≤5% change in GMRs; N = 27); norethindrone C(max) and AUC(0-inf) GMRs were higher (12 and 23%, respectively) with concomitant vismodegib. CONCLUSIONS: This DDI study in patients with cancer demonstrated that systemic exposure of rosiglitazone (a CYP2C8 substrate) or OC (ethinyl estradiol/norethindrone) is not altered with concomitant vismodegib. Overall, there appears to be a low potential for DDIs when vismodegib is co-administered with other medications.

User characteristics and out-of-pocket expenditures for progestin-only versus combined oral contraceptives.

BACKGROUND: Little is known about the proportion of oral contraceptive pill (OCP) users that use progestin-only pills (POPs), factors associated with POP use, and whether out-of-pocket expenditures and dispensing patterns are similar to combined oral contraceptives (COCs). STUDY DESIGN: Observational cohort using 1996-2008 Medical Expenditure Panel Surveys. RESULTS: Among all OCP users, 4% used POPs and changed little between 1996 and 2008. Women were more likely to use POPs if they received postpartum care (p<.001), had a diagnosis of hypertension (p<.001) or resided in the West (p<.01). POP users, compared to COC users, were more likely to pay $15 and more (p<.01) and less likely to obtain more than one pack per purchase (p<.001), controlling for age, race/ethnicity and insurance coverage. CONCLUSION: POP use is very low in the United States. POP users obtained fewer packs per purchase compared with COC users, suggesting that POP may be used as transitional OCPs, particularly during the postpartum period.

Quantification of the adverse effect of ethinylestradiol containing oral contraceptive pills when used in conjunction with growth hormone replacement in routine practice.

OBJECTIVE: Oestrogen antagonizes the action of growth hormone (GH). For women with combined GH and oestrogen deficiency, transdermal oestradiol is more favourable in this regard compared to oral oestradiol. Oral contraceptive pills containing ethinylestradiol (EE) are commonly used in young women with GHD and there is little information on the impact of this form of oestrogen. DESIGN: A case note review of women with growth hormone deficiency (GHD) attending a tertiary endocrine clinic comparing the dose of GH and serum insulin-like growth factor 1 concentrations and the type of exogenous oestrogen. METHODS: All women with GHD between the ages of 18 and 47 attending University College London Hospitals (UCLH) were included and grouped according to type of oestrogen replacement. Weight, GH dose and serum IGF-I concentrations were recorded at 121 visits in 88 women. RESULTS: The daily dose of GH was significantly higher and the GH responsivity was significantly lower in the EE group compared to those taking no oestrogen and transdermal oestrogen. The additional cost of GH for women using EE compared to transdermal oestradiol was £6016 per patient per year. Effectiveness of GH improved in all women changing from EE to another form of oestrogen. CONCLUSION: Use of oral contraceptive pills containing EE should be avoided in women receiving treatment with GH. Alternative options include oral or transdermal hormone replacement therapy (HRT) preparations for those that require oestrogen replacement or a progesterone-based regimen for contraceptive purposes.

Estradiol valerate/dienogest: a novel combined oral contraceptive.

BACKGROUND: Estradiol valerate/dienogest (E2V/DNG) is a combined oral contraceptive (COC) with 2 new hormonal entities and a unique 4-phasic dosing regimen indicated for women to prevent pregnancy. OBJECTIVE: The purpose of this article is to review the pharmacology, pharmacokinetics, clinical efficacy, tolerability, and cost of E2V/DNG. METHODS: MEDLINE (1966-June 2011) and EMBASE (1966-June 2011) were searched for original research and review articles published in the English language using the terms Natazia or Qlaira or estradiol valerate and dienogest. The reference lists of identified articles were reviewed for additional pertinent publications. Abstracts from the 2005 to 2011 American Society of Reproductive Medicine and American College of Obstetricians and Gynecologists meetings were searched using the same terms. RESULTS: The search provided 56 articles that addressed the pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, and tolerability of E2V/DNG in women of reproductive age. Articles reporting efficacy or tolerability in the setting of menopause were excluded. The initial efficacy of E2V/DNG on ovulation inhibition was investigated in 2 prospective, randomized, open-label, Phase II dose-finding studies. The dose that was approved by the Food and Drug Administration resulted in 3.13% of women ovulating in the second cycle of treatment (90% CI, 0.2%-6.05%). Rate of pregnancy prevention with this agent was reported with a Pearl Index ranging from 0.73 to 1.27 (unadjusted) to 0.34 to 0.72 (adjusted for method failure only). The mean duration of withdrawal bleeding was 4.3 days (range, 4.0-4.6 days) among 2266 women receiving 13 treatment cycles. Adverse events reported in >1% of patients included abdominal pain, acne, breast pain, dysmenorrhea, emotional lability, headache, nausea, and weight increase. CONCLUSIONS: Estradiol valerate/dienogest is a new contraceptive formulation. It offers efficacy, tolerability, and an acceptable safety profile with a potentially better bleeding pattern than levonorgestrel-containing COCs. This COC may be especially useful for older women of reproductive age who are adherent to therapy and looking for shorter and/or lighter menstrual cycles. Studies will need to be performed to determine whether clinically significant differences in outcomes exist among E2V/DNG and other available COCs.

Predictors of noncompliance in an oral contraceptive clinical trial.

BACKGROUND: This analysis was conducted to identify the participant characteristics associated with noncompliance in an oral contraceptive (OC) clinical trial. STUDY DESIGN: We studied ovarian suppression among normal-weight and obese women during the use of levonorgestrel (LNG)-containing combination OCs. Participants underwent twice weekly phlebotomy during the study cycle and received up to $360 for participation. Along with other study assays, we analyzed 903 specimens from 181 women to measure LNG to assess OC compliance. Consistently undetectable LNG levels indicated noncompliance. To evaluate predictors of OC noncompliance during this study, we compared the characteristics of compliant and noncompliant participants using multivariable logistic regression. We assigned each participant to a relative poverty level based on US census data; all other individual characteristics came directly from participant responses during the baseline interview. RESULTS: One hundred eighty-one women completed the study; 31 were noncompliant (17%). In multivariable analyses, poverty level was the strongest predictor of noncompliance. Compared with those women in the quartile with the lowest level of residential poverty, other women were far more likely to be noncompliant, especially women in the quartile with the greatest prevalence of poverty (adjusted odds ratio, 8.4; 95% confidence interval, 1.5-46.1). Additional factors associated with noncompliance were education level less than a bachelor's degree and Hispanic ethnicity. Other demographic and psychometric measures were not associated with compliance. CONCLUSIONS: We found that noncompliance was strongly associated with residential poverty level, an indirect measure of individual income. In the United States, poverty is associated with female obesity, Hispanic ethnicity and low education, which were also associated here with noncompliance. Study compensation may motivate poor individuals to participate in clinical trials for income. Noncompliance in clinical trials, particularly differential noncompliance, jeopardizes study validity.

Ovulation inhibition doses of progestins: a systematic review of the available literature and of marketed preparations worldwide.

BACKGROUND: The objective of this analysis was to provide a comprehensive review of ovulation inhibition data of progestins currently available worldwide. This analysis may serve as a reference tool for research on new progestin molecules. STUDY DESIGN: We used literature search engines to detect data of progestin monotherapies on ovulation inhibition in humans. Only treatments with stable dosing during a cycle were accepted. In a second step, we tried to estimate the 99% ovulation inhibiting doses and their fiducial confidence limits using the probit dose-response model. Finally, we analyzed the progestin doses of combined oral contraceptives currently on the market. RESULTS: We found original data on 29 marketed and nonmarketed progestins in a total of 60 publications, published between 1956 and May 2010. Details on methods used for determining ovulation, number of doses and daily dose of each tested progestin, number of subjects, cycles and ovulations are summarized in a table. We designed one example of a dose-response curve using the statistical model. For most progestins, literature data were insufficient for this purpose. A total of 13 progestins are components of oral contraceptives currently on the market worldwide, five of them in combination with 20 mcg ethinyl estradiol (EE). CONCLUSION: This review provides a comprehensive overview of all progestins ever tested for their ovulation inhibition potency and a summary of all preparations currently on the world market, including their regimens and their combinations with EE.

Hormonal contraception and area of cervical ectopy: a longitudinal assessment.

BACKGROUND: The effect of combined oral contraceptives (COCs) and depot-medroxyprogesterone acetate (DMPA) on the area of cervical ectopy is not well understood. STUDY DESIGN: From 1996 to 1999, we recruited women not using hormonal contraception from two family planning centers in Baltimore, MD. Upon study entry and 3, 6 and 12 months after the initial visit, participants were interviewed and received visual cervical examinations with photography. Ectopy was measured from digitized photographs and was analyzed both continuously and categorically (small [≤0.48 cm(2)] vs. large [>0.48 cm(2)]). RESULTS: Of 1003 enrolled women, 802 returned for at least one follow-up visit. At 12 months, the numbers of women using COCs, DMPA or no hormonal method at least 50% of the time since the prior visit were 230, 76 and 229, respectively. After multivariable adjustment, COC use (vs. no hormonal use) was associated with large area of ectopy (odds ratio [OR]: 1.8, 95% confidence interval [CI]: 1.0-3.3). No significant relationship was observed between DMPA and large area of ectopy (OR: 0.5, 95% CI: 0.2-1.3). The incidence of large area of ectopy by contraceptive exposure (COC, DMPA or no hormonal method) was 17.4 (CI: 11.8-24.6), 10.9 (CI: 4.4-22.4) and 4.6 (CI: 2.2-8.4) per 100 woman-years, respectively. CONCLUSIONS: Use of COCs, but not DMPA, was associated with large area of cervical ectopy. Area of ectopy at baseline was the strongest predictor of area of ectopy at follow-up.

[Routines for first prescription of oral contraceptives]. / Rutiner ved førstegangsforskrivning av p-piller.

BACKGROUND: There is an increasing awareness about the risk of thromboembolic disease caused by combination oral contraceptives. This study assesses routines associated with prescription of an oral contraceptive, with an emphasis on venous thromboembolic disease. MATERIAL AND METHODS: A questionnaire requesting information about medical history, examinations, and general routines when an oral contraceptive was prescribed for the first time was sent to general practitioners, public health nurses and midwives in two Norwegian counties in 2008. A slightly different questionnaire was distributed to a group of female medical students. They were requested to describe the queries, procedures and information they were subjected to when oral contraceptives was first prescribed for themselves. RESULTS: In total, 99-100% of the prescribers reported that they asked about smoking habits and venous thromboembolic disease in the family. 94% of the doctors and 100% of the public health nurses/midwives informed about the risk of venous thromboembolic disease (p=0.028). The students reported that they had been asked, examined and informed less often than that reported by health professionals. 54% of the physicians and 11% of the public health nurses /midwives most often prescribed third generation oral contraceptives (p < 0.001). INTERPRETATION: Doctors, midwives and public health nurses seem to examine and inform their patients thoroughly about the risk of venous thromboembolic complications when prescribing combination oral contraceptives for the first time. Public health nurses and midwives seem to have a more rational prescription pattern of combined oral contraceptives than doctors.

Long-term assessment of symptomatology and satisfaction of an extended oral contraceptive regimen.

OBJECTIVE: The study was conducted to assess hormone withdrawal symptoms, patient acceptance and occurrence and management of bleeding with an extended oral contraceptive (OC) regimen. METHODS: Subjects were placed on an OC containing 3 mg drosperinone (DRSP) and 30 microg ethinyl estradiol (EE), in the standard 21/7 fashion for two cycles, before converting to an extended pattern of OC for women who indicated they had menstrually related symptoms such as headaches, cramping and mood swings (52 weeks with phone-call follow-up 6 months later). Daily assessments of bleeding, headache, pelvic pain, mood and number of pain pills were recorded. Results are reported as means with S.E., and values were compared using analysis of variance with Dunnett's post hoc test for comparison with 21/7 cycle, Duncan's post hoc test for comparison of changes during the course of the extended regimen and Pearson's chi-square for comparison of proportions. RESULTS: Of the 111 women who began the extended OC regimen, 80 completed 1 year of use. Mood scores, headache scores and pelvic pain were all improved in the extended OC intervals, compared to the 21/7 cycle (p<.001 for all comparisons). Improvement in symptoms persisted throughout the 1 year extended regimen. The findings indicated that 53.7% of subjects had no breakthrough bleeding or breakthrough spotting (BTB/BTS) during any given 28-day interval of the extended regimen. BTB/BTS decreased in the second half compared to the first half of the extended regimen. To manage BTB/BTS, instituting a 3-day hormone-free interval (HFI) was significantly more effective than continuing OCs (p<.001). At the 6-month follow-up, most subjects had continued the extended regimen on their own with a high level of satisfaction. CONCLUSIONS: An extended OC regimen containing DRSP/EE significantly improved mood, headaches and pelvic pain scores throughout the 1 year of use, compared to a 21/7 cycle. Sustained BTB/BTS episodes occurred in 45 subjects (56%), decreasing in the second half of the study and effectively managed with a 3-day HFI.