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Background: With dramatic improvements in life expectancy for cystic fibrosis (CF) patients, contraception for women with CF has become an important issue. There are theoretical concerns that hormonal contraceptive use among women with CF may impact disease severity or risk for other adverse health outcomes, including thrombosis and poor bone health, as well as concerns that malabsorption or altered drug metabolism might impact contraceptive effectiveness., Objective: To evaluate evidence on the safety and effectiveness of contraceptive methods among women with CF., Search Strategy: We searched the PubMed database for all articles published from database inception through October 2015., Selection Criteria: We included studies that examined measures of disease severity, other health outcomes or indicators of contraceptive effectiveness among women with CF initiating or continuing a contraceptive method., Results: Seven studies met our inclusion criteria. Three observational studies of fair to poor quality suggest that use of oral contraceptives (OCs) does not negatively impact CF disease severity, defined as changes in pulmonary function, number of exacerbations or need for intravenous antibiotics. Three small studies of poor quality reported on contraceptive failure among women with CF using combined hormonal contraceptives (combined OCs, patch or ring). One pregnancy was reported in a patch user out of 43 hormonal contraceptive users across all studies. One pharmacokinetic study reported that women with CF achieve steroid hormone plasma concentrations similar to healthy women after ingestion of combined OCs., Conclusions: Limited evidence suggests that hormonal contraceptive use does not negatively impact disease severity among women with CF and that hormonal contraceptive effectiveness is not impaired by CF. Studies were limited by small sample sizes and short duration of follow-up. No studies examined the effect of hormonal contraception on thrombosis or bone health among women with CF., (Published by Elsevier Inc.)

Objective: To examine whether the co-administration of hormonal contraceptives (HC) and psychotropic drugs commonly used to treat anxiety and/or depression results in safety or efficacy concerns for either drug., Methods: We searched PubMed and Cochrane libraries for clinical or pharmacokinetic (PK) studies that examined co-administration of any HC with psychotropic drugs [selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), oral benzodiazepines, bupropion, mirtazapine, trazadone, buspirone, hydroxyzine, monoamine oxidase inhibitors (MAOIs), or atypical antipsychotics] in reproductive aged women., Results: Of 555 articles identified, 22 articles (18 studies) met inclusion criteria. We identified 5 studies on SSRIs, four on TCAs, one on bupropion, three on atypical antipsychotics and five on oral benzodiazepines. No articles met inclusion criteria for SNRIs, mirtazapine, trazadone, buspirone, hydroxyzine or MAOIs. Overall, clinical studies did not demonstrate differences in unintended pregnancy rates when HCs were administered with and without psychotropic drugs or in psychotropic drug treatment outcomes when psychotropic drugs were administered with and without HCs. PK studies did not demonstrate changes in drug exposure related to contraceptive safety, contraceptive effectiveness or psychotropic drug effectiveness for most classes of psychotropic drugs. However, limited PK data raise concern for HCs increasing systemic exposure of amitriptyline and imipramine (both TCAs), theoretically posing safety concerns., Conclusion: Limited quality and quantity evidence on use of psychotropic drugs and HCs suggests low concern for clinically significant interactions, though no data exist specifically for non-oral formulations of HC. Given the high frequency of use for both HCs and psychotropic drugs among reproductive-age women in the US, this review highlights a need for further research in this area., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Despite several drawbacks, the Pearl Index continues to be the most widely used statistical measure of contraceptive failure. However, Pearl indices reported in studies of newer hormonal contraceptives appear to be increasing., Study Design: We searched PubMed and Medical Intelligence Solutions databases for prospective trials evaluating oral contraceptive (OC) efficacy to examine potential factors that could contribute to increasing Pearl indices., Results: Numerous potential factors were identified, including an increased rate of failures of newer OCs, deficiencies in methods of calculating contraceptive failure rates, differences in study design and changes in patient populations resulting in increased rates of contraceptive failures due to the inappropriate or inconsistent use of the method., Conclusions: The two most likely important contributors to the increase in Pearl indices are more frequent pregnancy testing with more sensitive tests and less adherent study populations. Because study populations appear to be increasingly representative of the likely actual users once the product is marketed, we can expect to see even higher failure rates in ongoing and future studies. This result poses challenges for companies and regulatory agencies., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: This study analyzes levels of progesterone, estradiol, norethindrone (NET) and ethinyl estradiol (EE) in serum and levels of NET in cervical mucus on the last day of the hormone-free interval (HFI) in users of 24/4 [norethindrone acetate (NETA)/EE-24] vs. 21/7 (NETA/EE-21) regimens., Study Design: This was a randomized controlled, crossover, equivalency trial. Subjects were randomized to receive NETA/EE-24 or NETA/EE-21 for 2 months and then switched between study drugs. Blood and cervical mucus samples were obtained on Days 12-16 and on the last day of the HFI., Results: From April 2010 to November 2011, 32 subjects were enrolled with 18 subjects completing all study visits. There were no statistically significant differences in either day 12-16 (p=.54) or last hormone-free day (p=.33) cervical mucus NET concentrations between the regimens. On the last day of the HFI, median serum progesterone levels did not differ significantly; however, users of NETA/EE-24 had higher levels of serum NET (p<.001) and users of NETA/EE-21 had higher levels of serum estradiol (p=.01)., Conclusion: This data supports the fact that inhibition of the pituitary-ovarian axis occurs during oral contraceptive use and during the HFI. We demonstrated that a reduced HFI of 4 days resulted in better suppression of the ovarian hormone production, thereby reducing the risk of ovulation and potential contraceptive failure., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: We evaluated the effects of cytochrome P450 3A4 (CYP3A4) induction and inhibition on steady-state pharmacokinetics of the components of a novel oral contraceptive (OC) containing estradiol valerate (E₂V) and dienogest (DNG)., Study Design: CYP3A4 induction was assessed in an open-label, one-arm study. Sixteen healthy postmenopausal women received E₂V 2 mg/DNG 3 mg (days 1-17) and concomitant rifampicin (600 mg, days 12-16). Ratios of the area under the serum concentration-time curve between 0 and 24 h [AUC(0-24 h)] and maximum serum concentration (C(max)) of E₂ and DNG on days 17 and 11 (after and before rifampicin intervention) are presented. CYP3A4 inhibition was investigated in an open-label, parallel-group study in 24 healthy postmenopausal women receiving E₂V 2 mg/DNG 3 mg (days 1-14) and concomitant ketoconazole (400 mg, n=12) or erythromycin (500 mg three times daily, n=12) on days 8-14. Mean ratios of AUC(0-24 h) and C(max) of E₂ and DNG on days 7 and 14 are presented., Results: Concomitant administration of rifampicin decreased systemic drug exposure and yielded geometric mean ratios for E₂C(max) and AUC(0-24 h) of 75% and 56%, respectively. Corresponding mean ratios for DNG were 48% and 17%, respectively. Ketoconazole coadministration increased systemic drug exposure and yielded ratios of E₂ of 165% and 157%, respectively, and ratios of DNG of 194% and 286%, respectively. Erythromycin coadministration also resulted in increased mean C(max) and AUC(0-24 h) of both E₂ and DNG. Geometric mean ratios of C(max) and AUC(0-24 h) for E₂ were 151% and 133%, respectively. Corresponding ratios for DNG were 133% and 162%, respectively., Conclusions: Significant drug-drug interactions are apparent when CYP3A4 modulators are coadministered with the components of a novel OC containing E₂V/DNG. Coadministration of CYP3A4 modulators should be avoided where possible, and another type of contraception should be used when coadministration of CYP3A4 inducers like rifampicin is unavoidable., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The effect of obesity on drug metabolism and pharmacokinetics is poorly understood, and this is particularly true in regard to contraceptive steroids. This article will review the known and theoretical physiologic and pharmacologic interactions between obesity and contraceptive steroids., (Copyright © 2010 Elsevier Inc. All rights reserved.)

This open-label, randomized study compared the pharmacokinetics of ethinylestradiol (EE) from the contraceptive vaginal ring NuvaRing (15 microg EE/day), the transdermal patch (20 microg EE/day) and a combined oral contraceptive (COC) containing 30 microg EE. After 2-8 weeks of synchronization by COC treatment, subjects were randomized to 21 days of treatment with NuvaRing, patch or COC. Analysis of area under the EE concentration-versus-time curve (AUC) during 21 days of treatment showed that exposure to EE in the NuvaRing group was 3.4 times lower than in the patch group (p < .05) and 2.1 times lower than in the pill group (p < .05). Serum EE levels of subjects showed much lower variation with NuvaRing than with the patch or the COC. Thus, exposure to EE was significantly lower with NuvaRing than with the patch and pill methods, demonstrating that NuvaRing is a low-estrogen-dose contraceptive method that also results in low estrogen exposure.

Presently, the lowest effective estrogen dose available as a combination oral contraceptive (OC) in the United States is 20 microg of ethinyl estradiol (EE) with different progestins. Twenty micrograms of EE coupled with levonorgestrel results in fewer side effects and cycle control comparable with higher-dose pills. Differences between therapeutically equivalent and brand-name, low-dose oral contraceptives, with respect to the bioavailability of hormones, may interfere with contraceptive efficacy and increase breakthrough bleeding. One of the most common reasons why women discontinue OCs is increased breakthrough bleeding. Because after OC discontinuation most women switch to a less-effective method, or no method, of contraception, an increase in breakthrough bleeding could ultimately result in an increase in unintended pregnancy. Thus, substituting a therapeutically equivalent for a brand-name low-dose oral contraceptive may have significant clinical and economic effects on individual and public health.

Written guidelines for the preclinical testing of contraceptive steroids have not been revised since 1968 despite the fact that many important changes have been implemented by the FDA's Division of Metabolism and Endocrine Drug Products. This paper describes the new preclinical testing requirements and the rationale for their implementation.

A radioimmunoassay for the determination of gestodene (17-ethinyl-13-ethyl-17 beta-hydroxy-4,15-gonadien-3-one) in human plasma is described with regard to procedure, specificity, accuracy and reproducibility. Antiserum was raised against gestodene-3-O-(carboxymethyl)oxime-BSA in rabbits and [9,11-3H]-gestodene tracer was used with a specific radioactivity of 2.16 TBq/mmol. The final antiserum dilution was 1: 200,000. RIA was performed according to routine methods using diethylether plasma extracts and the charcoal separation technique. Cross-reactivity of antiserum with cortisol, 17 beta-estradiol, progesterone, testosterone and ethinylestradiol was less than 0.03%; levonorgestrel exhibited a 5% cross-reactivity. No cross-reactivity with metabolites of gestodene or ethinylestradiol was found. Accuracy and precision of the assay were tested using human plasma samples spiked with 1, 5 and 10 ng/ml gestodene. Accuracy was within 94 to 104% of the nominal values. Within-assay and between-assay coefficients of variation were in the range of 4.7-6.5% and 10.3-13.1%, resp. This RIA was used to follow plasma gestodene levels after single oral administration of 75 micrograms of gestodene combined with 30 micrograms ethinylestradiol as tablet and coated tablet in a cross-over design in 6 female test subjects. Plasma gestodene levels were equivalent after both treatments.

Serial studies were conducted in five women under norgestrel + EE-2 after interrupting 11-34 months of regular use of the medication. A venous blood and an endometrial sample were simultaneously obtained from each subject between the 22nd and 25th day of the pseudocycle (last month of contraception) and on the same days of the following three cycles under no treatment for the measurement of EE-2 content. Values during and after the first month of no medication were: plasma = 85 +/- 6 versus 218 +/- 36 (pg/ml; P less than 0.001) and endometrium = 93 +/- 10 versus 29 +/- 7 (ng/g wet tissue; P less than 0.001). A decrement of circulating EE-2 from 346 pg/ml in the first month with no medication to 14 pg/ml in the third month off the treatment was observed. The EE-2 endometrial uptake of 93 +/- 10 (last month of steroidal ingestion) decreased to 29 +/- 7, 7 +/- 2 and 4 +/- 0.9 ng/g wet tissue in the following three months of no treatment. In 3/15 instances after interrupting contraception, circulating EE-2 was below the detection limit of the assay, while endometrial EE-2 uptake was in the range of 3-19 ng/g wet tissue. These data confirm our apparent controversial report that EE-2 plasma levels increased during the first month after interrupting medication and support the presence of the exogenous estrogen in plasma and endometrium after interrupting the steroidal contraceptive for three months.

The serum concentrations of ethinylestradiol (EE) during the first 4 h and 24 h after intake of an oral contraceptive containing 30 micrograms EE and 75 micrograms gestodene (EE/GSD) were compared to those after intake of a preparation containing the same EE dose and 150 micrograms desogestrel (EE/DG) in each of 11 women on days 1, 10, and 21 of their 1st, 3rd, 6th, and 12th cycles. There were great interindividual variations, but during treatment with EE/GSD the EE levels were higher and the EE peaks occurred by 30 min later than during treatment with EE/DG. The areas under the EE serum concentration-versus-time curves (AUC) between 0 and 4 h were higher by 37% (p less than 0.03) and between 0 and 24 h higher by 70% (p less than 0.002) during treatment with EE/GSD. During each treatment cycle, the EE levels rose between day 1 and 10. The serum levels of corticosteroid-binding globulin (CBG), which is known to be influenced only by the estrogenic component of the combination pill, increased significantly (p less than 0.01) during each treatment cycle. CBG was elevated on day 21 of the 6th and 12th cycle by 150 to 155% and by 120 to 130% with EE/GSD and EE/DG, respectively. The difference between the two drugs was significant (p less than 0.02). During the pill-free intervals of 7 days between the treatment cycles, the CBG levels decreased but were still elevated by 85% with EE/GSD and 50% with EE/DG at the beginning of the following cycle as compared to the control cycle. The serum levels of cortisol were also significantly more elevated (p less than 0.05) during treatment with EE/GSD as compared to EE/DG. Despite the same EE dose during treatment, the higher EE levels with EE/GSD as compared to EE/DG seem to be due to a retardation of the inactivation and elimination of EE caused by the progestogen component. The rise in the EE levels during each cycle seems to be due to a reduction in the oxidative metabolism by EE itself.

We have examined the pharmacokinetic parameters derived from the analysis of plasma ethinyl estradiol (EE) and norethindrone levels after administration of a single dose of three bioequivalent norethindrone-1mg/mestranol (ME)-50 micrograms formulations (Ortho-NovumR 1/50, NorinylR 1/50 and Norcept-MR 1/50) and three norethindrone-1mg/ethinyl estradiol-35 micrograms formulations (Ortho-Novum 1/35R, NorinylR 1/35, Norcept-ER 1/35) in a randomized crossover design involving 24 women for the 35 micrograms and 27 women for the 50 micrograms agents. Differences between the AUC-EE of pairs from the same manufacturer (1 + 35 and 1 + 50) were not significantly different, indicating that 50 micrograms of mestranol was equivalent to 35 micrograms ethinyl estradiol with respect to this pharmacokinetic parameter. The Cmax values were also similar. Inter-individual coefficients of variation (C.V.) for the AUC-EE were 47% and 57% for the 1 + 35 and 1 + 50 agents, respectively. Intra-individual C.V.s were 41% and 42%, respectively. For norethindrone, the AUC was larger with the 1 + 50 formulations than with the 1 + 35 group (87.9 vs. 72.8 pg hr/ml). Additionally, the Cmax values were larger for the 1/50 group (17.7 vs. 14.0). Since the amount of norethindrone in the two dosage groups was the same, this difference in the pharmacokinetics between the 35 micrograms EE and the 50 micrograms ME formulations remains unexplained. The inter-individual C.V. averaged 56% for both dosage groups. The intra-individual C.V.s were 17% and 46% for the 1 + 35 and 1 + 50 groups, respectively. The large variation in blood levels of ethinyl estradiol and norethindrone between and within individuals may overshadow clinical differences attributable to differences in dosage.