ABSTRACT
INTRODUCTION: Norgestimate (NGM) is a testosterone derivative with peculiar receptor activities. AREAS COVERED: This is a narrative review of the available data on the pharmacotherapy of NGM in combined hormonal contraceptives (CHCs) in terms of contraceptive efficacy, venous thromboembolism (VTE) risk, safety, tolerability and bleeding patterns. A comprehensive literature review was conducted in August 2020 using PubMed with the keyword 'norgestimate'. EXPERT OPINION: NGM shows a mild estrogenic activity associated with anti-mineralocorticoid and anti-androgenic properties, largely responsible for the cardiovascular safety profile. The anti-androgenic property depends on the androgen receptor (AR) nuclear translocation (AR trafficking and its subnuclear distribution), the inhibition of 5α-reductase activity (it possesses higher activity compared to other available progestins), and the increase on sexual hormone binding globulin (SHBG) levels if combined with an estrogenic counterpart. NGM is one of the molecules that best modulates the power of ethinyl-estradiol on the thromboembolic risk, being associated with the lowest VTE risk between different CHCs. NGM has the advantage of retaining peripheral anti-androgenic activity, demonstrated by the impact on lipid and glucose metabolism, and it should be preferred if compared with other similar progestins of the same class of risk which are much more androgenic, such as levonorgestrel.
Subject(s)
Contraceptive Agents, Hormonal/administration & dosage , Norgestrel/analogs & derivatives , Venous Thromboembolism/chemically induced , Animals , Contraceptive Agents, Hormonal/adverse effects , Contraceptive Agents, Hormonal/pharmacology , Female , Humans , Levonorgestrel/administration & dosage , Levonorgestrel/adverse effects , Levonorgestrel/pharmacology , Norgestrel/administration & dosage , Norgestrel/adverse effects , Norgestrel/pharmacology , Risk , Venous Thromboembolism/epidemiologyABSTRACT
OBJECTIVE: To evaluate the bioequivalence of norelgestromin and ethinyl estradiol (NGMN-EE) and adhesion of a transdermal contraceptive patch containing a newly sourced adhesive component (test) compared with the marketed (reference) patch. STUDY DESIGN: In this randomized, double-blind, 2-way crossover study, healthy women received single 7-day application of both test and reference patches. Treatment phase included two treatment periods of 11 days each separated by a 21-day washout period starting from day of patch removal (day 8) of treatment period 1. Assessments included NGMN and EE pharmacokinetics (PK), adhesion using European Medicines Agency (EMA) 5-point scale, irritation potential and application-site reactions, and safety. Patches were bioequivalent if 90% CIs of ratios of means of test/reference for AUC168h, AUCinf, and Css fell within 80-125%. Patch adhesion was comparable if ratios of mean cumulative adhesion percentage values of test/reference were ≥90.0%. RESULTS: Seventy women were randomized; 57 completed both treatments with ≥80% adhesion (score 0-1). Bioequivalence of test and reference patches was demonstrated as 90% CI of ratio of geometric means for AUC168h, AUCinf, and Css for NGMN and EE fell within 80-125%. Both patches had similar adhesion properties (geometric mean ratio was 100.3% [90% CI, 93.2-107.9]). Similar rates of mild-to-moderate itching (11% vs 10%) and erythema events (79% vs 74%) were reported for test and reference patches, respectively, on day 8. CONCLUSIONS: The test patch with the newly sourced adhesive component is bioequivalent to the currently marketed NGMN-EE transdermal patch and has similar adhesion and irritation potential. IMPLICATIONS STATEMENT: The norelgestromin and ethinyl estradiol transdermal patch containing a newly sourced adhesive component is bioequivalent to the currently marketed patch for both active moieties. Both patches had similar adhesion, irritation potential, and safety profiles.
Subject(s)
Adhesives/adverse effects , Contraceptive Agents, Hormonal/pharmacokinetics , Ethinyl Estradiol/pharmacokinetics , Norgestrel/analogs & derivatives , Transdermal Patch/adverse effects , Adhesives/administration & dosage , Adult , Contraceptive Agents, Hormonal/administration & dosage , Contraceptive Agents, Hormonal/adverse effects , Cross-Over Studies , Double-Blind Method , Drug Combinations , Ethinyl Estradiol/administration & dosage , Ethinyl Estradiol/adverse effects , Female , Humans , Norgestrel/administration & dosage , Norgestrel/adverse effects , Norgestrel/pharmacokinetics , Therapeutic Equivalency , Transdermal Patch/standardsABSTRACT
BACKGROUND: Women are 2 to 9 times more likely to experience an anterior cruciate ligament (ACL) injury than men. Various hormones including relaxin, progesterone, and estrogen influence ACL strength. Oral contraceptives (OCs) alter these hormone levels; however, studies have yet to comprehensively compare different OCs' effects on the ACL. HYPOTHESIS: OCs with increased progestin-to-estrogen ratios will (1) increase ACL collagen expression, (2) decrease ACL matrix metalloproteinase expression, and (3) increase ACL strength. STUDY DESIGN: Controlled laboratory study. METHODS: Untreated female rats were compared with rats treated with 1 of 5 clinically used OCs: norethindrone (NE) only, NE plus ethinylestradiol (EE), etynodiol diacetate (ED) plus EE, norgestimate (NG) plus EE, and drospirenone (DS) plus EE. Doses were scaled from human doses to account for differences in bioavailability and body weight, and OCs were administered daily via oral gavage for 4 rat estrous cycles (20 days). A total of 36 rats were then sacrificed (6 rats/group). ACLs underwent biomechanical testing to assess ACL strength, stiffness, and maximum load before failure. ACL specimens were also isolated for quantitative real-time polymerase chain reaction analysis to assess collagen, matrix metalloproteinase, and relaxin receptor-1 expression. RESULTS: While the primary structural property of interest (ACL maximum load before failure) was not significantly improved by OC treatment, the main material property of interest (ACL strength) in rats treated with NE only, DS + EE, ED + EE, and NE + EE was significantly increased compared with untreated controls (P = .001, P = .004, P = .004, and P = .04, respectively). The order from strongest to weakest ACLs, which was also the same order as the highest to lowest progestin-to-estrogen ratios, was groups treated with NE only, DS + EE, ED + EE, NE + EE, and lastly NG + EE. Higher ratio formulations also increased the expression of type I collagen (P = .02) and decreased the expression of matrix metalloproteinase-1 (P = .04). CONCLUSION: OC formulations with higher progestin-to-estrogen ratios may be more protective for the ACL than formulations with lower ratios. CLINICAL RELEVANCE: OC formulations with high progestin-to-estrogen ratios may benefit female athletes by reducing their ACL injury risk by decreasing the effects of relaxin on the ACL.
Subject(s)
Anterior Cruciate Ligament/physiology , Contraceptives, Oral/administration & dosage , Estrogens/analysis , Progestins/analysis , Androstenes/administration & dosage , Animals , Biomechanical Phenomena , Ethinyl Estradiol/administration & dosage , Ethynodiol Diacetate/administration & dosage , Female , Norethindrone/administration & dosage , Norgestrel/administration & dosage , Norgestrel/analogs & derivatives , Rats , Rats, Sprague-DawleyABSTRACT
INTRODUCTION: AG200-15, an investigational transdermal contraceptive delivery system or patch, is designed to be a low-dose, non-daily, combined hormonal contraceptive option for women. In this phase 1 study, the in vivo adhesion of the AG200-15 patch was compared to Xulane®, the only contraceptive patch available in the USA. METHODS: This phase 1, randomized, open-label, single-dose, two-treatment, two-period crossover adhesion study compared the 7-day adhesion of the AG200-15 and Xulane contraceptive patches. Eighty-three women, ages 18 to 35 years old, with body mass index (BMI) ≥ 19 kg/m2 and < 35 kg/m2, and weight ≥ 48 kg and < 90 kg were enrolled. Trained study site personnel used a five-point scale to assess patch adhesion daily. A score of 0 reflected at least 90% adhesion; while a score of 4 represented complete detachment of the patch. The primary objective was to compare the adhesion properties of the two patches; AG200-15 would be considered statistically non-inferior to Xulane if the upper 95% confidence limit (CL) of the mean difference in adhesion scores was below + 0.15. RESULTS: The overall mean (standard deviation) scores for AG200-15 (N = 78) and Xulane (N = 77) were 0.14 (0.28) and 0.39 (0.40), respectively (lower scores on the adhesion scale indicate better adhesion). The study demonstrated a difference in mean adhesion scores of - 0.24, meeting the prespecified non-inferiority criterion by demonstrating a one-sided upper CL of - 0.16. Thus, the in vivo adhesion of AG200-15 was shown to be non-inferior to that of Xulane. Most subjects experienced no skin irritation at the application site for either patch and no serious adverse event was reported in the study. CONCLUSION: The in vivo adhesion of AG200-15 is non-inferior to that of Xulane on the basis of the prespecified criterion of the upper bound of the one-sided 95% CL for the mean adhesion score difference being below + 0.15. Both patches were generally well tolerated. FUNDING: Agile Therapeutics, Inc.
Subject(s)
Contraceptive Agents/therapeutic use , Ethinyl Estradiol/therapeutic use , Levonorgestrel/therapeutic use , Norgestrel/analogs & derivatives , Administration, Cutaneous , Adolescent , Adult , Body Mass Index , Contraceptive Agents/administration & dosage , Contraceptive Agents/adverse effects , Cross-Over Studies , Dose-Response Relationship, Drug , Drug Combinations , Equivalence Trials as Topic , Ethinyl Estradiol/administration & dosage , Ethinyl Estradiol/adverse effects , Female , Humans , Levonorgestrel/administration & dosage , Levonorgestrel/adverse effects , Norgestrel/administration & dosage , Norgestrel/adverse effects , Norgestrel/therapeutic use , Oximes/administration & dosage , Oximes/adverse effects , Oximes/therapeutic use , Young AdultABSTRACT
BACKGROUND: Erenumab is a human anti-calcitonin gene-related peptide monoclonal antibody developed for migraine prevention. Migraine predominately affects women of childbearing age; thus, it is important to determine potential drug-drug interactions between a common oral contraceptive and drugs used to treat migraine. OBJECTIVES: We sought to evaluate potential drug-drug interactions between erenumab and a common oral contraceptive. METHODS: Healthy women received three cycles of a norgestimate/ethinyl estradiol-containing oral contraceptive with a single 140-mg subcutaneous dose of erenumab during cycle three. Norgestimate metabolites (norgestrel and norelgestromin) and ethinyl estradiol pharmacokinetics were evaluated in the absence and presence of erenumab. Primary endpoint was peak plasma concentration (Cmax) and area under concentration-time curve from time 0 to 24 h (AUCtau). Luteinizing hormone, follicle-stimulating hormone, and progesterone concentrations were evaluated as pharmacodynamic markers. RESULTS: Erenumab did not influence the pharmacokinetics of norelgestromin, norgestrel, or ethinyl estradiol. Least-squares mean estimates (90% confidence interval) for Cmax ratios were 1.05 (0.90-1.23), 1.06 (0.97-1.16), and 1.04 (0.88-1.22) for norelgestromin, norgestrel, and ethinyl estradiol, respectively. Respective AUCtau ratios were 1.02 (0.94-1.12), 1.03 (0.96-1.10), and 1.02 (0.91-1.14). Luteinizing hormone, follicle-stimulating hormone, and progesterone concentrations were similar after exposure to oral contraceptive alone and with erenumab. CONCLUSION: Erenumab did not alter the pharmacokinetics of the active components of an estrogen/progestin combination oral contraceptive. Thus, no change in contraceptive efficacy is expected with erenumab. TRIAL REGISTRATION: ClinicalTrials.gov NCT02792517.
Subject(s)
Antibodies, Monoclonal, Humanized/blood , Calcitonin Gene-Related Peptide Receptor Antagonists/blood , Contraceptives, Oral, Combined/blood , Ethinyl Estradiol/blood , Norgestrel/analogs & derivatives , Adolescent , Adult , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/pharmacology , Area Under Curve , Calcitonin Gene-Related Peptide Receptor Antagonists/administration & dosage , Calcitonin Gene-Related Peptide Receptor Antagonists/adverse effects , Calcitonin Gene-Related Peptide Receptor Antagonists/pharmacology , Contraceptives, Oral, Combined/administration & dosage , Contraceptives, Oral, Combined/adverse effects , Contraceptives, Oral, Combined/pharmacology , Drug Combinations , Drug Interactions , Ethinyl Estradiol/administration & dosage , Ethinyl Estradiol/adverse effects , Ethinyl Estradiol/pharmacology , Female , Follicle Stimulating Hormone/blood , Healthy Volunteers , Humans , Luteinizing Hormone/blood , Metabolic Clearance Rate , Middle Aged , Norgestrel/administration & dosage , Norgestrel/adverse effects , Norgestrel/blood , Norgestrel/pharmacology , Progesterone/blood , Young AdultABSTRACT
Delayed-release dimethyl fumarate (DMF) is an oral therapy for relapsing multiple sclerosis with anti-inflammatory and neuroprotective properties. This 2-period crossover study was conducted to evaluate the potential for drug-drug interaction between DMF (240 mg twice daily) and a combined oral contraceptive (OC; norgestimate 250 µg, ethinyl estradiol 35 µg). Forty-six healthy women were enrolled; 32 completed the study. After the lead-in period (OC alone), 41 eligible participants were randomized 1:1 to sequence 1 (OC and DMF coadministration in period 1; OC alone in period 2) or sequence 2 (regimens reversed). Mean concentration profiles of plasma norelgestromin (primary metabolite of norgestimate) and ethinyl estradiol were superimposable following OC alone and OC coadministered with DMF, with 90% confidence intervals of geometric mean ratios for area under the plasma concentration-time curve over the dosing interval and peak plasma concentration contained within the 0.8-1.25 range. Low serum progesterone levels during combined treatment confirmed suppression of ovulation. The pharmacokinetics of DMF (measured via its primary active metabolite, monomethyl fumarate) were consistent with historical data when DMF was administered alone. No new safety concerns were identified. These results suggest that norgestimate/ethinyl estradiol-based OCs may be used with DMF without dose modification.
Subject(s)
Dimethyl Fumarate/administration & dosage , Ethinyl Estradiol/administration & dosage , Immunosuppressive Agents/administration & dosage , Norgestrel/analogs & derivatives , Administration, Oral , Adult , Area Under Curve , Contraceptives, Oral, Combined , Cross-Over Studies , Delayed-Action Preparations , Dimethyl Fumarate/pharmacokinetics , Drug Combinations , Drug Interactions , Ethinyl Estradiol/pharmacokinetics , Female , Fumarates/pharmacokinetics , Humans , Immunosuppressive Agents/pharmacokinetics , Maleates/pharmacokinetics , Norgestrel/administration & dosage , Norgestrel/blood , Norgestrel/pharmacokinetics , Oximes/blood , Young AdultABSTRACT
Combined estrogen-progestin preparations (CEPs) are associated with thromboembolic (TE) side effects. The aim of this study was to evaluate the incidence of TE using the Japanese Adverse Drug Event Report (JADER) database. Adverse events recorded from April 2004 to November 2014 in the JADER database were obtained from the Pharmaceuticals and Medical Devices Agency (PMDA) website (www.pmda.go.jp). We calculated the reporting odds ratios (RORs) of suspected CEPs, analyzed the time-to-onset profile, and assessed the hazard type using Weibull shape parameter (WSP). Furthermore, we used the applied association rule mining technique to discover undetected relationships such as the possible risk factors. The total number of reported cases in the JADER contained was 338,224. The RORs (95% confidential interval, CI) of drospirenone combined with ethinyl estradiol (EE, Dro-EE), norethisterone with EE (Ne-EE), levonorgestrel with EE (Lev-EE), desogestrel with EE (Des-EE), and norgestrel with EE (Nor-EE) were 56.2 (44.3-71.4), 29.1 (23.5-35.9), 42.9 (32.3-57.0), 44.7 (32.7-61.1), and 38.6 (26.3-56.7), respectively. The medians (25%-75%) of the time-to-onset of Dro-EE, Ne-EE, Lev-EE, Des-EE, and Nor-EE were 150.0 (75.3-314.0), 128.0 (27.0-279.0), 204.0 (44.0-660.0), 142.0 (41.3-344.0), and 16.5 (8.8-32.0) days, respectively. The 95% CIs of the WSP-ß for Ne-EE, Lev-EE, and Nor-EE were lower and excluded 1. Association rule mining indicated that patients with anemia had a potential risk of developing a TE when using CEPs. Our results suggest that it is important to monitor patients administered CEP for TE. Careful observation is recommended, especially for those using Nor-EE, and this information may be useful for efficient therapeutic planning.
Subject(s)
Drug-Related Side Effects and Adverse Reactions/genetics , Estrogens/administration & dosage , Estrogens/adverse effects , Progestins/administration & dosage , Progestins/adverse effects , Thromboembolism/chemically induced , Adolescent , Adult , Adverse Drug Reaction Reporting Systems , Androstenes/administration & dosage , Androstenes/adverse effects , Child , Contraceptives, Oral, Combined/administration & dosage , Contraceptives, Oral, Combined/adverse effects , Databases, Factual , Desogestrel/administration & dosage , Desogestrel/adverse effects , Ethinyl Estradiol/administration & dosage , Ethinyl Estradiol/adverse effects , Female , Humans , Japan , Levonorgestrel/administration & dosage , Levonorgestrel/adverse effects , Male , Middle Aged , Norethindrone/administration & dosage , Norethindrone/adverse effects , Norgestrel/administration & dosage , Norgestrel/adverse effects , Odds Ratio , Young AdultABSTRACT
Estrous synchronization with progesterone based protocols has been essentially used in cattle industry. Although intravaginal devices have been commonly used, this technique may induce vaginitis. This study aimed at examining the efficiency of novel transdermal progestin patch on follicle development and comparing the progestin patch versus CIDR device on estrous synchronization, complication at treated site and pregnancy in beef cattle. In experiment 1, seven beef cows were treated with an adhesive transdermal progestin patch on the ventral surface of the proximal part of the tail for 7 days. The cows were daily examined the follicular development using ultrasonography starting on Day 0 till 3 days after hormone removal. Experiment 2, forty beef cows were divided into two equal groups (20 cows per group). The cows randomly allocated to received either vaginal insertion of CIDR (n = 20) or treated with an adhesive transdermal progestin patch (n = 20). The levels of plasma progesterone during the experiment and the numbers of standing estrous cows were recorded. Timed artificial inseminated (TAI) was performed at 60 h after CIDR or patch termination. Pregnancy rates were determined at 60 days after TAI. Experiment 1 revealed that the novel transdermal progestin patch could efficiently control follicular growth. All the seven treated cows had dominant follicle upon dermal patch removal indicating the effectiveness of the progestin patch. In experiment 2, the percentages of cows exhibited standing estrus were similar between transdermal patch (72.22%) and CIDR (70.00%). The levels of plasma progesterone during CIDR treatment were significantly higher (4.06 ± 1.65 ng/mL on Day 1 and 3.62 ± 1.60 ng/mL on Day 7) compared with transdermal patch (2.60 ± 1.43 ng/mL on Day 1 and 1.81 ± 1.57 ng/mL on Day 7). Three cows treated with CIDR (15%) developed vaginitis while none of cows had physically dermal reaction at adhesive site. Cows synchronized with these two protocols had similar pregnancy rates (50.00%) following fixed time artificial insemination. It is concluded that transdermal progestin patch was equally effective in estrus synchronization as compared with traditional CIDR. However, the transdermal patch demonstrated less complication. This device should therefore be considered as an alternative method for estrus synchronization in postpartum beef cattle.
Subject(s)
Cattle/physiology , Dinoprost/analogs & derivatives , Estrus Synchronization/methods , Ethinyl Estradiol/pharmacology , Norgestrel/analogs & derivatives , Administration, Cutaneous , Administration, Intravaginal , Animals , Dinoprost/administration & dosage , Dinoprost/pharmacology , Drug Combinations , Estrus/drug effects , Ethinyl Estradiol/administration & dosage , Female , Insemination, Artificial/veterinary , Norgestrel/administration & dosage , Norgestrel/pharmacology , PregnancyABSTRACT
BACKGROUND: We performed a pilot evaluation of a new formulation of levonorgestrel butanoate (LB) designed to be a long-acting injectable (6 months) contraceptive to determine pharmacodynamic end points in normal-body mass index (BMI) and obese women. STUDY DESIGN: Obese (BMI ≥30 kg/m2) and normal-BMI, otherwise healthy, women received a single intramuscular injection of LB after ovulation was confirmed in a baseline cycle. The primary outcome was return of ovulation in days. RESULTS: A total of 14 women enrolled and completed the study [normal BMI n=9, median BMI 22.7kg/m2 (range 19.4-25.8); obese n=5, median BMI 35.7kg/m2 (30.1-39.2)]. The first 6 subjects (normal BMI=4/9, obese BMI=2/5) received 40 mg of LB, and the remaining 8 received 20 mg. All women except one returned to ovulation prior to 6 months. Return to ovulation occurred earlier in the obese group; 3/5 obese and 0/9 normal BMI subjects returned to ovulation within 90 days (p=.03). No serious adverse events were reported during the study. CONCLUSION: Return to ovulation was earlier than 6 months in both BMI groups but more so in the obese BMI group. IMPLICATIONS: Since return of ovulation was earlier than expected for this LB injectable formulation, additional steps are needed to develop a preparation suitable as a longer-lasting product.
Subject(s)
Contraceptive Agents, Female/pharmacokinetics , Norgestrel/analogs & derivatives , Obesity/blood , Ovulation/drug effects , Adult , Body Mass Index , Body Weight/drug effects , Contraceptive Agents, Female/administration & dosage , Female , Humans , Injections, Intramuscular , Kaplan-Meier Estimate , Norgestrel/administration & dosage , Norgestrel/pharmacokinetics , Oregon , Pilot Projects , Prospective Studies , Time Factors , Young AdultABSTRACT
Retinitis pigmentosa (RP) is a degenerative retinal disease leading to photoreceptor cell loss. In 2011, our group identified the synthetic progesterone 'Norgestrel' as a potential treatment for RP. Subsequent research showed Norgestrel to work through progesterone receptor membrane component 1 (PGRMC1) activation and upregulation of neuroprotective basic fibroblast growth factor (bFGF). Using trophic factor deprivation of 661W photoreceptor-like cells, we aimed to further elucidate the mechanism leading to Norgestrel-induced neuroprotection. In the present manuscript, we show by flow cytometry and live-cell immunofluorescence that Norgestrel induces an increase in cytosolic calcium in both healthy and stressed 661Ws over 24 h. Specific PGRMC1 inhibition by AG205 (1 µm) showed this rise to be PGRMC1-dependent, primarily utilizing calcium from extracellular sources, for blockade of L-type calcium channels by verapamil (50 µm) prevented a Norgestrel-induced calcium influx in stressed cells. Calcium influx was also shown to be bFGF-dependent, for siRNA knock down of bFGF prevented Norgestrel-PGRMC1 induced changes in cytosolic calcium. Notably, we demonstrate PGRMC1-activation is necessary for Norgestrel-induced bFGF upregulation. We propose that Norgestrel protects through the following pathway: binding to and activating PGRMC1 expressed on the surface of photoreceptor cells, PGRMC1 activation drives bFGF upregulation and subsequent calcium influx. Importantly, raised intracellular calcium is critical to Norgestrel's protective efficacy, for extracellular calcium chelation by EGTA abrogates the protective effects of Norgestrel on stressed 661W cells in vitro.
Subject(s)
Calcium Signaling/drug effects , Fibroblast Growth Factor 2/metabolism , Norgestrel/administration & dosage , Photoreceptor Cells/drug effects , Photoreceptor Cells/metabolism , Progesterone/analogs & derivatives , Stress, Physiological/drug effects , Animals , Cell Line , Membrane Proteins/metabolism , Mice , Progesterone/administration & dosage , Receptors, Progesterone/metabolismABSTRACT
Retinitis pigmentosa (RP) is one of the most common retinal degenerative conditions affecting people worldwide, and is currently incurable. It is characterized by the progressive loss of photoreceptors, in which the death of rod cells leads to the secondary death of cone cells; the cause of eventual blindness. As rod cells die, retinal-oxygen metabolism becomes perturbed, leading to increased levels of reactive oxygen species (ROS) and thus oxidative stress; a key factor in the secondary death of cones. In this study, norgestrel, an FDA-approved synthetic analog of progesterone, was found to be a powerful neuroprotective antioxidant, preventing light-induced ROS in photoreceptor cells, and subsequent cell death. Norgestrel also prevented light-induced photoreceptor morphological changes that were associated with ROS production, and that are characteristic of RP. Further investigation showed that norgestrel acts via post-translational modulation of the major antioxidant transcription factor Nrf2; bringing about its phosphorylation, subsequent nuclear translocation, and increased levels of its effector protein superoxide dismutase 2 (SOD2). In summary, these results demonstrate significant protection of photoreceptor cells from oxidative stress, and underscore the potential of norgestrel as a therapeutic option for RP.
Subject(s)
Antioxidants/administration & dosage , NF-E2-Related Factor 2/metabolism , Norgestrel/administration & dosage , Retinal Degeneration/drug therapy , Animals , Antioxidants/pharmacology , Cell Nucleus/metabolism , Disease Models, Animal , Mice , NF-E2-Related Factor 2/genetics , Norgestrel/pharmacology , Phosphorylation , Retinal Degeneration/etiology , Retinal Degeneration/genetics , Retinal Degeneration/metabolism , Signal Transduction/drug effects , Superoxide Dismutase/genetics , Superoxide Dismutase/metabolism , Up-RegulationABSTRACT
BACKGROUND: Data on combined hormonal oral contraceptives' (OCs) effects on metabolic changes in women with polycystic ovary syndrome (PCOS) have been conflicting and were predominantly based on OCs with cyproterone acetate (unavailable in the United States) Most studies did not include normal women as controls. We compared metabolic changes before and after an OC commonly used in the United States between women with and without PCOS. METHODS: Ten PCOS and 20 control women took ethinyl estradiol 35 µg and norgestimate 0.18/0.215/0.25 mg. Fasting glucose and insulin, area-under-the-curve (AUC) glucose and insulin, insulin sensitivity (homeostatic model assessment of insulin sensitivity index [HOMA-ISI] and Matsuda index), insulinogenic index (Δinsulin0-30 minutes/Δglucose0-30 minutes), blood pressure, and lipids were evaluated at baseline and after three cycles of OC. RESULTS: At baseline, PCOS women had lower insulin sensitivity (Matsuda index p = 0.0093, HOMA-ISI p = 0.0397), higher fasting insulin (p = 0.0495), fasting glucose (p = 0.0393), AUC insulin (p = 0.0023), and triglycerides (p = 0.0044) versus controls. Baseline AUC glucose did not differ between PCOS women and controls. After 3 months of OC use, glucose tolerance worsened in PCOS women versus controls (p = 0.0468). Higher baseline androgens were predictive of worsened glucose tolerance, and a reduction of AUC insulin during OC use. The insulinogenic index significantly decreased in PCOS women (p < 0.01), while fasting insulin and insulin resistance significantly worsened in control women. CONCLUSION: Women with PCOS exhibited worsened glucose tolerance (demonstrated by AUC glucose) after 3 months of a commonly used OC compared with control women. Larger studies with longer follow-up should confirm these findings.
Subject(s)
Blood Glucose/metabolism , Contraceptives, Oral, Combined/pharmacology , Contraceptives, Oral, Hormonal/pharmacology , Contraceptives, Oral/pharmacology , Lipid Metabolism/drug effects , Norgestrel/analogs & derivatives , Polycystic Ovary Syndrome/drug therapy , Polycystic Ovary Syndrome/metabolism , Adult , Blood Glucose/drug effects , Carbohydrates/blood , Case-Control Studies , Contraceptives, Oral/administration & dosage , Contraceptives, Oral, Combined/administration & dosage , Contraceptives, Oral, Hormonal/administration & dosage , Dose-Response Relationship, Drug , Estrogens/administration & dosage , Ethinyl Estradiol/administration & dosage , Ethinyl Estradiol/pharmacology , Female , Glucose Tolerance Test , Gonadal Steroid Hormones/blood , Humans , Insulin/blood , Lipids/blood , Norgestrel/administration & dosage , Norgestrel/pharmacology , Polycystic Ovary Syndrome/physiopathologyABSTRACT
More than 50 interventions have been used to treat hidradenitis suppurativa (HS), and so therapy decisions can be challenging. Our objective was to summarize and appraise randomized controlled trial (RCT) evidence for HS interventions in adults. Searches were conducted in Medline, Embase, CENTRAL, LILACS, five trials registers and abstracts from eight dermatology conferences until 13 August 2015. Two review authors independently assessed study eligibility, extracted data and assessed methodological quality. Primary outcomes were quality of life and adverse effects of the interventions. Twelve trials, from 1983 to 2015, investigating 15 different interventions met our inclusion criteria. The median trial duration was 16 weeks and the median number of participants was 27. Adalimumab 40 mg weekly improved the Dermatology Life Quality Index (DLQI) by 4·0 points, which equates to the minimal clinically important difference for the scale, compared with placebo (95% confidence interval -6·5 to -1·5 points). Evidence quality was reduced to 'moderate' because the results are based on only a single study. Adalimumab 40 mg every other week was ineffective in a meta-analysis of two studies comprising 124 participants. Infliximab 5 mg kg(-1) improved the DLQI score by 8·4 points after 8 weeks in a moderate-quality study completed by 33 of 38 participants. Etanercept 50 mg twice weekly was ineffective. Inclusion of a gentamicin sponge prior to primary closure did not improve outcomes. Other interventions, including topical and oral antibiotics, were investigated by relatively small studies, preventing treatment recommendations due to imprecision. More, larger RCTs are required to investigate most HS interventions, particularly oral treatments and surgical therapy. Moderate-quality evidence suggests that adalimumab given weekly and infliximab are effective, whereas adalimumab every other week is ineffective.
Subject(s)
Hidradenitis Suppurativa/drug therapy , Adalimumab/administration & dosage , Administration, Oral , Adult , Androgen Antagonists/administration & dosage , Anti-Bacterial Agents/administration & dosage , Clindamycin/administration & dosage , Cyproterone Acetate/administration & dosage , Dermatologic Agents/administration & dosage , Etanercept/administration & dosage , Ethinyl Estradiol/administration & dosage , Gentamicins/administration & dosage , Humans , Infliximab/administration & dosage , Norgestrel/administration & dosage , Quality of Life , Treatment Outcome , Wound Closure TechniquesABSTRACT
INTRODUCTION: The first contraceptive patch with ethinyl estradiol (EE) and norelgestromin in the United States demonstrated that there was a tremendous interest in topical methods, which could provide patient convenience, steady-state hormonal levels and reassurance of ongoing coverage, while maintaining efficacy and good bleeding patterns. Unfortunately, concerns about increased risk of venous thromboembolism (VTE) risk diminished its popularity. Another version in Europe and Canada had slightly lower estrogen doses, but questions were raised about its VTE risk too based on its progestin. To fill that gap, two new contraceptive patches with lower estrogen levels have been developed and extensively tested. AREAS COVERED: This article provides a short overview of the first set of patches followed by discussions of the pharmacokinetics of the two experimental patches as well as the results of their clinical trials, including information about efficacy, bleeding patterns and tolerability. EXPERT OPINION: Given the recent increased use of first tier contraceptive methods (Intrauterine devices and implants), there may be interest in new patches. Price will influence their popularity. However, a new nondaily delivery system with lower estrogen levels will provide an important option to women.
Subject(s)
Contraceptive Agents, Female/administration & dosage , Contraceptives, Oral, Combined/administration & dosage , Administration, Cutaneous , Animals , Clinical Trials, Phase III as Topic , Contraceptive Agents, Female/adverse effects , Contraceptive Agents, Female/pharmacokinetics , Contraceptives, Oral, Combined/adverse effects , Contraceptives, Oral, Combined/pharmacokinetics , Drug Combinations , Ethinyl Estradiol/administration & dosage , Ethinyl Estradiol/adverse effects , Female , Humans , Levonorgestrel/administration & dosage , Levonorgestrel/adverse effects , Norgestrel/administration & dosage , Norgestrel/adverse effects , Norgestrel/analogs & derivatives , Norpregnenes/administration & dosage , Norpregnenes/adverse effectsABSTRACT
OBJECTIVE(S): To investigate the bleeding pattern and cycle control parameters of a contraceptive patch containing 0.55 mg ethinyl estradiol (EE) and 2.1 mg gestodene (GSD) compared with a patch containing 0.6 mg EE and 6 mg norelgestromin (NGMN). STUDY DESIGN: In this phase III, open-label, randomized, parallel-group trial, healthy women aged 18-35 years (smokers aged 18-30 years) received either the EE/GSD patch (n=200) or the EE/NGMN patch (n=198). Treatment consisted of one patch per week for 3 weeks followed by a 7-day, patch-free interval for seven cycles. Bleeding control was assessed in two 90-day reference periods. RESULTS: In reference period 1, mean number of bleeding/spotting days was comparable across treatment groups (p>0.05). However, in reference period 2, there were fewer bleeding/spotting days in the EE/GSD patch group (15.7 versus 18.4; p<0.0001). Mean number of bleeding/spotting episodes was comparable across groups for both reference periods, but bleeding/spotting episodes were shorter for the EE/GSD patch than the EE/NGMN patch during reference period 1 (5.13 days versus 5.53 days, respectively; p<0.05) and reference period 2 (5.07 versus 5.66; p=0.0001). Both treatment groups showed a similar frequency of withdrawal bleeding episodes; however, across all seven cycles, the length of these episodes was consistently shorter with the EE/GSD patch (p<0.01). There were no notable treatment differences in intracyclic bleeding. CONCLUSION(S): Bleeding pattern and cycle control achieved with the EE/GSD patch was similar to that of the EE/NGMN patch. IMPLICATIONS STATEMENT: The paper presents data on the bleeding pattern and cycle control parameters of an investigational transdermal contraceptive patch containing EE and GSD compared with an approved contraceptive patch containing EE and NGMN. This descriptive study found that bleeding patterns associated with the EE/GSD patch were similar to those of an EE/NGMN patch providing higher EE exposure.
Subject(s)
Contraceptive Agents, Female/administration & dosage , Estrogens/administration & dosage , Ethinyl Estradiol/administration & dosage , Menstrual Cycle/drug effects , Norpregnenes/administration & dosage , Progestins/administration & dosage , Transdermal Patch , Adolescent , Adult , Amenorrhea/chemically induced , Amenorrhea/epidemiology , Austria/epidemiology , Contraceptive Agents, Female/adverse effects , Czech Republic/epidemiology , Drug Combinations , Estrogens/adverse effects , Ethinyl Estradiol/adverse effects , Female , Humans , Incidence , Mastodynia/chemically induced , Mastodynia/epidemiology , Menorrhagia/chemically induced , Menorrhagia/epidemiology , Metrorrhagia/chemically induced , Metrorrhagia/epidemiology , Netherlands/epidemiology , Norgestrel/administration & dosage , Norgestrel/adverse effects , Norgestrel/analogs & derivatives , Norpregnenes/adverse effects , Patient Dropouts , Progestins/adverse effects , Transdermal Patch/adverse effects , Young AdultABSTRACT
OBJECTIVE: To compare the combination spironolactone-norgestimate-ethinyl estradiol in hirsutism with other protocols including the same dose of estrogen. STUDY DESIGN: In this open prospective study, 167 women with hirsutism due to polycystic ovary syndrome (PCOS) were randomly assigned to the following treatment protocols: Group A (n = 72): spironolactone 100 mg-norgestimate 250 mcg-ethinyl estradiol 35 microg; Group B (n = 70): cyproterone acetate 12 mg-ethinyl estradiol 35 microg; Group C (n = 25): norgestimate 250 microg-ethinyl estradiol 35 microg. RESULTS: The decrease in the hirsutism score was higher in group A than in the other groups (p < 0.001) and comparable in groups B and C. The decrease in acne score, androgen and estradiol levels, and ovary volume was similar in groups A and B. C-reactive protein increase was similar in all groups, but the augmentation of fibrinogen (p = 0.04), triglycerides (p < 0.01), monocyte count (p = 0.04), platelet number (p < 0.001) and mean volume (p = 0.01) was more pronounced in group B than in group A. Low-density lipoprotein/high-density lipoprotein cholesterol ratio decreased in groups A and C. CONCLUSION: Spironolactone-norgestimate-ethinyl estradiol is an effective and well-tolerated combination for the treatment of hirsutism in PCOS, with a favorable influence on lipids and indices of low-grade inflammation.
Subject(s)
Estrogens/therapeutic use , Hirsutism/drug therapy , Norgestrel/analogs & derivatives , Polycystic Ovary Syndrome/drug therapy , Spironolactone/therapeutic use , Adult , Drug Therapy, Combination , Estrogens/administration & dosage , Female , Hirsutism/epidemiology , Humans , Norgestrel/administration & dosage , Norgestrel/therapeutic use , Polycystic Ovary Syndrome/epidemiology , Spironolactone/administration & dosage , Testosterone/blood , Treatment Outcome , Young AdultABSTRACT
Uterine arteriovenous malformation (AVM) can cause sudden massive hemorrhage. We report a case of uterine AVM following curettage in a patient treated conservatively with an intermediate-dose pill. An 18-year-old gravida 2 para 0 underwent curettage at 12 weeks of gestation and was examined for massive genital hemorrhage that occurred in postoperative month 4. Abundant blood flow in a mass within the uterine lumen was observed on color Doppler ultrasonography, and the patient was diagnosed with AVM. Six days after starting oral norgestrel/ethinyl estradiol, the hemorrhage ceased, and computed tomography on day 37 of administration showed disappearance of the abnormal vasculature. After 12 months, the patient's course remains favorable without relapse. Transarterial embolization for AVM can cause ovarian failure and subsequent placental malpositioning. Administration of oral norgestrel/ethinyl estradiol may be an alternative conservative treatment option for patients who wish to maintain fertility.
Subject(s)
Arteriovenous Malformations/drug therapy , Contraceptives, Oral, Synthetic/administration & dosage , Ethinyl Estradiol/administration & dosage , Norgestrel/administration & dosage , Uterine Artery/abnormalities , Abortion, Induced/adverse effects , Adolescent , Arteriovenous Malformations/complications , Female , Humans , Uterine Hemorrhage/etiologyABSTRACT
BACKGROUND: The contraceptive skin patch (CSP) accepted by the U.S. FDA in 2001 includes ethinylestradiol and norelgestromine, whereas the subdermal contraceptive implant (SCI) has etonogestrel and is also approved by the FDA. In Mexico, both are now widely used for contraception but their effects on Mexican population are unknown. The objective of the study was to evaluate if these treatments induce metabolic changes in a sample of indigenous and mestizo Mexican women. METHODS: An observational, prospective, longitudinal, non-randomized study of women between 18 and 35 years of age assigned to CSP or SCI. We performed several laboratory tests: clinical chemistry, lipid profile, and liver and thyroid function tests. Also, serum levels of insulin, C-peptide, IGF-1, leptin, adiponectin, and C reactive protein were assayed. RESULTS: Sixty-two women were enrolled, 25 used CSP (0 indigenous; 25 mestizos) and 37 used SCI (18 indigenous; 19 mestizos). Clinical symptoms were relatively more frequent in the SCI group. Thirty-four contraceptive users gained weight without other clinical significant changes. After 4 months of treatment, significant changes were found in some biochemical parameters in both treatment groups. Most were clinically irrelevant. Interestingly, the percentage of users with an abnormal atherogenic index diminished from 75% to 41.6% after follow-up. CONCLUSIONS: The CSP slightly modified the metabolic variables. Most changes were nonsignificant, whereas for SCI users changes were more evident and perhaps beneficial. Results of this attempt to evaluate the effects of contraceptives in mestizo and native-American populations show that clinical symptoms are frequent in Mexican users of CSP and SCI. Although these medications may affect some metabolic variables, these changes seem clinically irrelevant. Induction of abnormalities in other physiological pathways cannot be ruled out.
Subject(s)
Contraceptive Agents, Female/adverse effects , Desogestrel/adverse effects , Ethinyl Estradiol/adverse effects , Norgestrel/analogs & derivatives , Adiponectin/blood , Adult , C-Peptide/blood , C-Reactive Protein/metabolism , Contraceptive Agents, Female/administration & dosage , Desogestrel/administration & dosage , Drug Combinations , Ethinyl Estradiol/administration & dosage , Female , Humans , Insulin/blood , Insulin-Like Growth Factor I/metabolism , Leptin/blood , Lipid Metabolism/drug effects , Liver Function Tests , Longitudinal Studies , Mexico , Norgestrel/administration & dosage , Norgestrel/adverse effects , Oximes/administration & dosage , Oximes/adverse effects , Thyroid Function Tests , Transdermal Patch , Weight Gain/drug effectsABSTRACT
BACKGROUND: Daclatasvir is a highly selective NS5A replication complex inhibitor currently in development for the treatment of chronic hepatitis C infection. Daclatasvir is active at picomolar concentrations and demonstrates in vitro activity against a broad range of HCV genotypes. The primary objective of this study was to assess the effect of daclatasvir on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and norgestimate (Ortho Tri-Cyclen(®)). METHODS: In this open-label single-sequence study, 20 healthy female subjects received ethinyl estradiol and norgestimate for three cycles, with coadministration of daclatasvir in cycle 3. Pharmacokinetics of ethinyl estradiol and the active metabolites of norgestimate (norelgestromin and norgestrel) were assessed in cycles 2 and 3. RESULTS: Adjusted ratios of geometric means and 90% CIs were estimated for the maximum observed plasma concentration (ethinyl estradiol 1.11 [1.02, 1.20], norelgestromin 1.06 [0.99, 1.14] and norgestrel 1.07 [0.99, 1.16]) and area under the plasma concentration-time curve in one dosing interval (ethinyl estradiol 1.01 [0.95, 1.07], norelgestromin 1.12 [1.06, 1.17] and norgestrel 1.12 [1.02, 1.23]). CONCLUSIONS: Coadministration of daclatasvir resulted in no clinically relevant effects on exposure to ethinyl estradiol, norelgestromin or norgestrel.