Norethindrone/Ethinyl Estradiol

Rationale: Epidemiologic studies demonstrate worse outcomes in women with cystic fibrosis (CF) than men. Women are colonized earlier with respiratory pathogens and have increased rates of pulmonary exacerbations after puberty and near ovulation. The etiology of this disparity is unclear, but sex hormones may contribute to these differences.Objectives: We sought to explore whether natural hormonal fluctuations and hormonal contraception associate with changes in lung function, respiratory symptoms, or inflammatory markers.Methods: We prospectively followed women with CF who were not on hormonal contraceptives and reported regular menstrual cycles. We captured study visits at points that corresponded with menses, ovulation, and the luteal phase. A subset of subjects were subsequently placed on a standard oral estrogen/progesterone combination contraceptive pill, ethinyl estradiol/norethindrone (loestrin), and reevaluated. Measurements included lung function, symptom questionnaires, sweat tests, blood for hormone concentrations, and sputum for inflammatory markers, bacterial density, and cytology.Results: Twenty-three women participated in this study. Hormone concentrations were as expected on and off hormonal contraception. At times of peak estrogen (ovulation), there was a significant increase in sputum proinflammatory cytokines (neutrophil-free elastase) and a corresponding pattern of decrease in lung function. Proinflammatory cytokines (IL-8, TNF-α, and neutrophil-free elastase) improved when placed on hormone contraception.Conclusions: Our results show that there are potentially important fluctuations in inflammatory biomarkers in the lungs that correlate with changes in lung function in women with CF. Larger studies evaluating the impact of sex hormones on airway inflammation and immune response are necessary to better understand the clinical impact of these responses.

It is limiting and potentially damaging to consider that women should not be prescribed combined oral contraceptives or progestin-only pills when concurrently taking certain antiretrovirals, based on our limited understanding of drug-to-drug interactions. Instead, a woman should be empowered and educated to access the combination of healthcare behaviors and medications that optimize her well-being and safety. Additionally, scientists, drug developers, and clinicians should strive to collaborate to responsibly synthesize our scientific data into a sound physiologic framework. The progestin component of hormonal contraceptives thickens cervical mucus and prevents sperm from entering the upper genital tract. Hostile cervical mucus is the primary mechanism by which hormonal contraceptives prevent pregnancy [1]. It is reasonable to infer that an elevated or maintained progestogen level with the co-administration of protease inhibitors would result in thickened and impenetrable cervical mucus with maintained contraception. Combined hormonal contraception typically contains ethinylestradiol (EE) in addition to a progestogen. The added EE is considered to have additional mechanisms of action, such as ovulation suppression, and offers a more favorable side effect profile, with less irregular bleeding [2]. Drug interactions that result in decreased EE serum concentrations should not have an impact on cervical mucus if the progestogen exposure is maintained. Furthermore, women are currently prescribed products with 10 lg EE doses, such as Lo Loestrin Fe, and are not specifically counseled on reduced contraceptive efficacy due to lower potential EE exposure. Contraceptive efficacy as defined by the Pearl Index in FDA trials, or typical use as defined by epidemiologic population-based data, are not determined by secondary markers and pharmacokinetic outcomes, such as those defined in the review by Tittle et al. [3] Clinicians and researchers should consider engaging in a discussion that explores the potential disparities between statistical and clinical significance, with the goal of executing research that focused on clinically significant measures. A mean area under the concentration-time curve difference of 10, 20, or 40 % may not be a clinically significant change, especially if that component was developed to minimize breakthrough bleeding or side effect profiles. If one of my patients requests combined oral contraceptives but is taking an interacting medication, I offer guidance and alternatives, and counsel on the benefits of long-acting reversible contraception, in addition to the use of condoms. If she does not have a contraindication, I prescribe her method of choice, with close follow-up and repeat counseling. I applaud Tittle et al. [3] for their eloquent and replete compilation of our peer-reviewed research regarding antiretrovirals and oral contraceptives. However, I caution that we lack robust epidemiologic data to conclude, in several instances, that efficacy is reduced. We must strive for better research and equitable interpretation of the data to engender access and enhanced reproductive justice for our HIV-positive women.