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Microarray patches (MAPs) offer a noninvasive and patient-friendly drug delivery method, suitable for self-administration, which is especially promising for low- and middle-income country settings. This study focuses on the development of dissolving bilayer MAPs loaded with norelgestromin (NGMN) as a first step towards developing a future potential drug delivery system for sustained hormonal contraception. The fabricated MAPs were designed with the appropriate needle lengths to penetrate the stratum corneum, while remaining minimally stimulating to dermal nociceptors. Ex vivo assessments showed that the MAPs delivered an average of 176 ± 60.9 μg of NGMN per MAP into excised neonatal porcine skin, representing 15.3 ± 5.3% of the loaded drug. In vivo pharmacokinetic analysis in Sprague Dawley rats demonstrated a Tmax of 4 h and a Cmax of 67.4 ± 20.1 ng/mL for the MAP-treated group, compared to a Tmax of 1 h and a Cmax of 700 ± 138 ng/mL for the intramuscular (IM) injection group, with a relative bioavailability of approximately 10% for the MAPs. The MAP-treated rats maintained plasma levels sufficient for therapeutic effects for up to 7 days after a single application. These results indicate the potential of NGMN-loaded dissolving bilayer MAPs, with further development focused on extending the release duration and improving bioavailability for prolonged contraceptive effects. [ABSTRACT FROM AUTHOR]

Microarray patches (MAPs) offer a noninvasive and patient-friendly drug delivery method, suitable for self-administration, which is especially promising for low- and middle-income country settings. This study focuses on the development of dissolving bilayer MAPs loaded with norelgestromin (NGMN) as a first step towards developing a future potential drug delivery system for sustained hormonal contraception. The fabricated MAPs were designed with the appropriate needle lengths to penetrate the stratum corneum, while remaining minimally stimulating to dermal nociceptors. Ex vivo assessments showed that the MAPs delivered an average of 176 ± 60.9 μg of NGMN per MAP into excised neonatal porcine skin, representing 15.3 ± 5.3% of the loaded drug. In vivo pharmacokinetic analysis in Sprague Dawley rats demonstrated a Tmax of 4 h and a Cmax of 67.4 ± 20.1 ng/mL for the MAP-treated group, compared to a Tmax of 1 h and a Cmax of 700 ± 138 ng/mL for the intramuscular (IM) injection group, with a relative bioavailability of approximately 10% for the MAPs. The MAP-treated rats maintained plasma levels sufficient for therapeutic effects for up to 7 days after a single application. These results indicate the potential of NGMN-loaded dissolving bilayer MAPs, with further development focused on extending the release duration and improving bioavailability for prolonged contraceptive effects.

The disease caused by SARS-CoV-2 is still considered a global pandemic. Transdermal patches (TP) with immunoregulators such as estrogen and progesterone compounds could be a feasible option to treat COVID-19 because of their accessibility and relative safety. The objective of the current study was to evaluate the additional treatment with norelgestromin and ethinylestradiol in TP on the clinical and biochemical evolution of COVID-19 patients. The present is a clinical-trial pilot study that included subjects diagnosed with COVID-19, randomized into two groups; the experimental Evra® TP (norelgestromin 6 mg and ethinylestradiol 0.60 mg) was administered such that it was applied on arrival and replaced at day 8 and day 15. The control continued with the conventional COVID-19 treatment protocol. A blood sample was taken each week in order to evaluate relevant biochemical parameters, clinical signs, and evolution. In total, 44 subjects participated in this study, 30 in the experimental group and 14 in the control group. Both groups were homogeneous in terms of age and comorbidities. The experimental group had a significantly lower hospital stay (p = 0.01), high flow supplemental oxygen (p = 0.001), mechanical ventilation (p = 0.003), and intubation (p = 0.01), and the oxygen saturation significantly increased (p = 0.01) in comparison with control group when patients were exposed to room air. A decrease in ferritin (p < 0.05) was observed, with no significant increase in ESR (p > 0.05), D dimer (p > 0.05) and platelets (p > 0.05) in an auto-controlled analysis in the experimental group. Norelgestromin and ethinylestradiol TP could be a safe and effective treatment for moderate and severe COVID-19 patients. [ABSTRACT FROM AUTHOR]

The disease caused by SARS-CoV-2 is still considered a global pandemic. Transdermal patches (TP) with immunoregulators such as estrogen and progesterone compounds could be a feasible option to treat COVID-19 because of their accessibility and relative safety. The objective of the current study was to evaluate the additional treatment with norelgestromin and ethinylestradiol in TP on the clinical and biochemical evolution of COVID-19 patients. The present is a clinical-trial pilot study that included subjects diagnosed with COVID-19, randomized into two groups; the experimental Evra® TP (norelgestromin 6 mg and ethinylestradiol 0.60 mg) was administered such that it was applied on arrival and replaced at day 8 and day 15. The control continued with the conventional COVID-19 treatment protocol. A blood sample was taken each week in order to evaluate relevant biochemical parameters, clinical signs, and evolution. In total, 44 subjects participated in this study, 30 in the experimental group and 14 in the control group. Both groups were homogeneous in terms of age and comorbidities. The experimental group had a significantly lower hospital stay (p = 0.01), high flow supplemental oxygen (p = 0.001), mechanical ventilation (p = 0.003), and intubation (p = 0.01), and the oxygen saturation significantly increased (p = 0.01) in comparison with control group when patients were exposed to room air. A decrease in ferritin (p < 0.05) was observed, with no significant increase in ESR (p > 0.05), D dimer (p > 0.05) and platelets (p > 0.05) in an auto-controlled analysis in the experimental group. Norelgestromin and ethinylestradiol TP could be a safe and effective treatment for moderate and severe COVID-19 patients.

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. [ABSTRACT FROM AUTHOR]

The article presents data on a study of transdermal therapeutic system with 600 mkg ethinylestradiol and 6000 mkg norelgestromin, which was used for removal vasomotor and neuropsychiatric disorders of severe and middle course of climacteric syndrome. Purpose: to assess the effectiveness of influence of transdermal therapeutic system with 600 mkg ethinylestradiol and 6000 mkg norelgestromin for vasomotor and neuropsychiatric disorders of severe and middle climacteric syndrome. Materials and methods. 103 women of postmenopausal age with severe and middle climacteric disorders were under observation: 65 of them were included into the main group, 38 – the comparison group. Severity stage of climacteric manifestation was determined according to menopause rating scale (MRS) before treatment and a month after treatment. Women of the main group were offered to treat climacteric disorders with TTS, which contains 600 mkg ethinylestradiol and 6000 mkg norelgestromin, in regime 1 patch per 1 month. Traditional MHT preparation was prescribed to the women of the comparison group, this drug contains 1mg ethinylestradiol and 5 mg dydrohesteron, per os route in uninterrupted regime. Results. It was found reduction of vegetative, vascular and neuropsychiatric menopausal symptoms and total index of menopause from 25.9 ± 1.2 to 8.2 ± 0.9 – in the main group; and from 25.4 ± 1.6 to 9.9 ± 1.2 – in the comparison group. Reliable difference (p < 0.05) was found out after treatment between indexes of the main and comparison groups according to such criteria, as: hot flashes, sleeping disorders, joint and muscle complaints, depression, anxiety. These indexes were mush better in the main group. Conclusions. During treatment of severe and middle climacteric syndrome with TTS, which contains 600 mkg ethinylestradiol and 6000 mkg norelgestromin (Evra plaster), rapid and durable correction of vegetative, vascular and neuropsychiatric climacteric disorders was found out. Reliable reduction of total index of menopause in a month after treatment by 68.3 % from the first index (in the comparison group – 61 %) allows to recommend TTS with ethinylestradiol and norelgestromin as independent correction method for severe and middle climacteric disorders tratment. climacteric; psychoneuroses; ethinylestradiol; norelgestromin

Objectives: We sought to assess the change in serum ethinyl estradiol (EE2) and norelgestromin (NGMN) levels over 12 weeks of continuous contraceptive patch use.Study Design: We asked participants (n=30) to apply consecutive patches to be worn continuously (without a patch-free interval) for 12 weeks. We collected blood samples at the end of each patch week and two times during weeks 4, 8, and 12 (with the additional blood draw occurring mid-week). Liquid chromatography-tandem triple quadrupole mass spectrometry (LC-MS/MS) was utilized to assess EE2 and NGMN levels.Results: Twenty-seven women completed the study; 26 were compliant with patch use. Ethinyl estradiol levels ranged from 0 to 193 pg/mL over the period. We observed an accumulation over the 12-week time at an estimated rate of 2.15 pg/mL per week (95% confidence interval 0.95-3.35, p<.001). The change in NGMN levels ranged from 0 to 2.52 ng/mL over the 12 weeks (95% confidence interval 0.021-0.019, p=.915). The most common side effects reported were vaginal spotting, breast tenderness and abdominal pain/cramping. There were no serious adverse events reported.Conclusion: While the range of weekly EE2 values was quite wide, the absolute values remain low and generally within the expected range described in product labeling. Providers may consider prescribing continuous use of the patch, but given the slow accumulation of EE2 over time, 12 weeks should not be exceeded in the absence of safety data. [ABSTRACT FROM AUTHOR]

Norelgestromin/ethinyl estradiol is a progestin/estrogen combination hormonal contraceptive indicated for the prevention of pregnancy in women. The very poor solubility and wettability of these drugs, along with their high potency (adsorption issues), give rise to difficulties in designing intravenous (IV) formulations to assess absolute bioavailability of products containing both drugs. The purpose of this study was to develop an IV formulation, evaluate its stability under different conditions and evaluate its compatibility with IV sets for potential use in absolute bioavailability studies in humans. Also, a selective high-performance liquid chromatography (HPLC) method for quantification of ethinyl estradiol and norelgestromin in polysorbate 80 matrix was developed and validated. Norelgestromin/ethinyl estradiol IV solution was prepared using sterile water for injection with 2.5% ethanol and 2.5% polysorbate 80 as a cosolvent/surfactant system to obtain a final drug solution of 25 μg ethinyl estradiol and 252 μg norelgestromin from a concentrated stock drug solution. The stabilities of the concentrated stock and IV solutions were assessed after storing them in the refrigerator (3.7 ± 0.6 °C) and at room temperature (19.5 ± 0.5 °C), respectively. Additional studies were conducted to examine the stability of the IV solution using an Alarias ® low sorbing IV administration set with and without an inline filter. The solution was allowed to drip at 1 mL/min over a 60 min period. Samples were obtained at the beginning, middle and end of the 60 min duration. The chemical stability was evaluated for up to 10 days. Norelgestromin and ethinyl estradiol concentration, purity, and degradant levels were determined using the HPLC method. The norelgestromin/ethinyl estradiol IV formulation met the chemical stability criteria when tested on day 1 through day 9 (216 h). Norelgestromin concentrations assayed in stock and IV solutions were in the range of 90.0–98.5% and 90.9–98.8% after 9 days, respectively. As for ethinyl estradiol, the assayed concentrations were in the range of 91.8–100.9% and 92.7–100.8% for the stock and IV solutions, respectively. The administration set was found to be compatible with both drugs; the assayed concentrations were in the range of 99.2–100.3% for norelgestromin and 96.3–102.7% for ethinyl estradiol, but the inline filter showed some adsorption of ethinyl estradiol; where the assayed concentrations were in the range of 98.1–99.8% for norelgestromin and 95.9–97.4% for ethinyl estradiol. The present study provided evidence supporting the suitability of an intravenous formulation for norelgestromin/ethinyl estradiol using ethanol/polysorbate 80 as a cosolvent/surfactant system. Both IV and concentrated stock solutions when stored at room temperature and refrigeration, respectively, were found to be chemically stable up to 9 days. These results indicated that this formulation is chemically stable and can be used over the time period tested. This IV formulation can be used to evaluate the absolute bioavailability of products containing norelgestromin and ethinyl estradiol provided that microbial testing of the IV formulation is performed. [ABSTRACT FROM AUTHOR]

Contraceptive patches have become a frequently used contraceptive method. We present a mathematical model that describes the serum concentration profiles of Norelgestromin (NGMN) and Ethinylestradiol (EE) released from the contraceptive patch Ortho Evra®. We propose a simple one-compartment model based on pharmacokinetics data reported in previous studies. The model assumes a time-dependent release rate and a first order elimination rate for each of the active ingredients contained in the patch. The model was applied to noncompliance scenarios, such as total and partial detachment of the patch or prolonged use without patch replacement. The proposed model adequately describes the clinically observed evolution of NGMN and EE in serum. Predictions from the model were successfully validated using reported experimental data of serum concentrations of NGMN and EE. This simple model can be a valuable tool to predict pharmacokinetic profiles in diverse scenarios such us non-compliance situations. Alternatively, the model can be conveniently adapted to anticipate the effect of variations on patch characteristics such as differences in contact area, doses, materials, among others [ABSTRACT FROM AUTHOR]

Objective A systematic review of studies published between January 1995 and April 2010 aimed at determining the effect of combined hormonal contraceptives (CHCs), administered orally, transdermally or vaginally, on the risk of venous thromboembolism (VTE). Results Of the 625 potentially eligible references reviewed, 25 studies meeting the inclusion and exclusion criteria were entered in the meta-analysis. The pooled relative risks of VTE associated with the various CHCs, depending on their progestogen, were: gestodene vs. levonorgestrel 1.33 (95% confidence interval [CI]: 1.08-1.63); desogestrel vs. levonorgestrel 1.93 (95% CI: 1.31-2.83); and drospirenone vs. levonorgestrel 1.67 (95% CI: 1.10-2.55). The pooled adjusted odds ratio for norgestimate vs. levonorgestrel was 1.11 (95% CI: 0.84-1.46) and that for cyproterone acetate vs. levonorgestrel 1.65 (95% CI: 1.30-2.11). Conclusions The safest CHCs in terms of VTE are those containing levonorgestrel or norgestimate. The risk of VTE associated with desogestrel-, drospirenone- or cyproterone acetate-containing CHCs is greater than that associated with CHCs containing levonorgestrel. The increased risk of VTE found for CHCs with gestodene compared to CHCs with levonorgestrel seems smaller than in previous analyses. There were no differences in VTE risk between oral and transdermal CHCs containing norgestimate or norelgestromin, respectively. [ABSTRACT FROM AUTHOR]

Combination hormonal contraception, particularly the oral contraceptive, is one of the most widely used reversible methods worldwide. However, improper use contributes significantly to unintended pregnancy. The purpose of this article is to review relevant clinical data to support the use of the transdermal contraceptive patch as a method of birth control. The transdermal contraceptive patch provides a weekly dosing approach without sacrificing efficacy. The frequency of side effects is similar to that experienced by oral contraceptive users, although certain side effects, for example, breast tenderness and skin irritation, are more common among patch users. Although there has been concern that the transdermal contraceptive patch may be associated with higher rates of venous thromboembolism than other combination contraceptive methods, study results are not consistent, and the rates of venous thromboembolism are significantly lower than those experienced by pregnant women. [ABSTRACT FROM AUTHOR]

Abstract: A simple, sensitive and rapid method is presented for the determination of norelgestromin using LC–MS/MS, interfaced via an electrospray ionization (ESI) probe, operating in the positive ion mode with multiple reaction monitoring (MRM). The method was developed and validated over the concentration range of 0.05–20ng/ml, and showed excellent linearity. The intra- and inter-assay accuracy error and precision were ranging from −2.3% to 6.0% of nominal values and 2.2% to 7.8% over the three concentration levels evaluated. The concentration of formic acid in mobile phase was optimized to achieve satisfactory injection reproducibility and sensitivity, and sample preparation was optimized, with only 1.6ml organic solvents used in performing the liquid–liquid extraction. The method has been successfully applied to a pharmacokinetic study of the ORTHO EVRA® patch in rabbits. [Copyright &y& Elsevier]

Taranabant, an orally active, potent, and highly selective CB-1 receptor inverse agonist, is being developed for the treatment of obesity. This randomized, placebocontrolled, multiple-dose, crossover study evaluated the effect of taranabant on the pharmacokinetics of ethinyl estradiol and norelgestromin in healthy women receiving =3 months of therapy with oral contraceptives. Nineteen participants with normal menstrual cycles received oral contraceptives on days 1 to 21 during 2 consecutive contraceptive cycles. Participants received taranabant 6 mg/day or placebo on days 1 to 21 of each contraceptive cycle. Plasma samples were collected predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose on day 21 of each cycle for determination of AUC[sub0-24 h] and C[submax] of ethinyl estradiol and norelgestromin. Lack of a clinically important effect was declared if the 90% confidence intervals for the geometric mean ratio of AUC[sub0-24 h] and C[submax] in the absence and presence of taranabant were contained within the predefined bounds of (0.8, 1.25). The geometric mean ratios and 90% confidence intervals of ethinyl estradiol and norelgestromin, respectively, were 0.93 (0.87, 1.00) and 1.02 (0.96, 1.09) for AUC[sub0-24 h] and 0.95 (0.88, 1.01) and 0.95 (0.88, 1.01) for C[submax]. In summary, coadministration of multiple-dose taranabant 6 mg with oral contraceptives did not lead to clinically meaningful alterations in the pharmacokinetic profiles of ethinyl estradiol or norelgestromin. [ABSTRACT FROM AUTHOR]

The article discusses some of the commonly-used transdermal contraceptive patch. These contraceptive patches contain two hormones, ethinyl estradiol and norelgestromin. It has been found to have advantages such as transdermal application and maintenance of adequate hormonal levels for at least seven days. It has similar side effects to oral contraceptives except for breast tenderness in the first two months and skin irritation at the application site.

In a randomized trial, the effects on sex hormone-binding globulin (SHBG), corticosteroid-binding globulin (CBG), thyroxin-binding globulin (TBG) and C-reactive protein (CRP) of three cycles of treatment with a contraceptive patch containing ethinylestradiol (EE) and norelgestromin versus treatment with an oral contraceptive (OC) containing EE and norgestimate were compared. There was a significantly higher increase in the levels of SHBG and TBG during treatment with the patch than with the OC, whereas the estrogen-induced rise in CBG and CRP was similar. The results suggest a higher impact on estrogen-sensitive hepatic proteins of the contraceptive patch than of an OC due to the higher exposure of the women to EE. It has been reported that the relative risk of venous thromboembolism increases during treatment with the transdermal contraceptive patch to a similar extent as with OC. [ABSTRACT FROM AUTHOR]

The function and clinical significance of the androgen receptor (AR) in human breast cancer are still not clear. The synthetic progestins, norgestimate and norelgestromin, were designed to minimize the adverse effects such as acne, hirsuitism and metabolic changes observed with older oral contraceptives while maintaining contraceptive effectiveness and cycle control. AR-mediated effects of these synthetic progestins were studied in an in vitro transactivation assay, employing DNA co-transfection of an AR expression vector and luciferase reporter gene construct in the MDA-MB 231 human breast cancer cell line. Testosterone acetate and 5α-dihydrotestosterone induced the reporter gene transcription, whereas incubation of the transfected cells with the natural progestin 17α-hydroxyprogesterone did not markedly induce luciferase activity. The progestins norgestimate and norelgestromin exerted a very low androgenic activity. Our data suggest that norgestimate and its metabolite norelgestromin possess weak androgen-like properties. The use of these compounds for clinical application may be of great advantage in the treatment of breast cancer as well as hyperandrogenism in women. [ABSTRACT FROM AUTHOR]

Over 16 million women in the United States take oral hormonal contraceptives, yet approximately 5% experience an unintended pregnancy during the first year of use. Compliance with the regimen is important in maintaining cycle control and preventing pregnancy. New hormonal contraceptive agents, norelgestromin-ethinyl estradiol patch, etonogestrel-ethinyl estradiol vaginal ring, and medroxyprogesterone-estradiol cypionate injection, were designed to increase compliance and decrease adverse effects while maintaining efficacy. Each one has potential advantages for women seeking alternatives to traditional oral contraceptives or for those who have trouble remembering to take a daily pill. Each agent also may have its own disadvantages, including application site reactions, need for monthly injections, and device-related events; however, all have similar efficacy and adverse-effect profiles compared with current oral hormonal contraceptives. [ABSTRACT FROM AUTHOR]

: ObjectiveTo compare the effects of the contraceptive patch to oral contraceptives (OCs) on follicular size and incidence of ovulation in normal cycles and after dosing errors.: DesignRandomized, open-label.: SettingTwelve centers.: Patient(s)One hundred twenty-four ovulatory women.: Intervention(s)Subjects received either the patch (groups 1 and 2) or one of three OCs. Correct dosing occurred in cycles 1, 2, 3, and 5. The following dosing errors were planned during cycle 4, a shortened 10-day cycle: [1] patch group 1 subjects wore one patch for 10 consecutive days; [2] for patch group 2 and OC subjects, 7 dosing days were followed by 3 drug-free days.: Main outcome measure(s)Follicular size, as determined at each cycle by the maximum mean follicular diameter.: Result(s)After a 3-day dosing error, follicular size was significantly smaller in the patch group (mean, 7.0 mm) vs. each OC group (range of means, 11.8–17.1 mm). Similar results were seen after proper dosing. The incidence of ovulation was significantly lower for the patch users than for women using OCs.: Conclusion(s)Follicular size and incidence of ovulation were significantly reduced among contraceptive patch users compared with women using OCs in normal cycles and after planned dosing errors. [Copyright &y& Elsevier]

Norelgestromin (NGMN) and levonorgestrel (LNG) are the main active metabolites of norgestimate (NGM), but their relative contributions to the pharmacological effects of NGM are unclear. We have therefore determined the serum distribution of these NGM metabolites and assessed their steady-state concentrations in women following ≥3 cycles of oral contraceptive (OC) use. The administration of 250 μg NGM/35 μg ethinyl estradiol (EE) resulted in significantly higher sex hormone-binding globulin (SHBG) levels (p = 0.002), and 30% lower serum non-protein-bound (NPB) levels of testosterone, when compared to treatment with 150 μg LNG/30 μg EE. We also confirmed that NGMN does not bind to SHBG, and found that 97.2% of this metabolite is bound to albumin while only 2.8% is in the NPB fraction. In contrast, most of the LNG was bound to SHBG (92.5% and 87.2% after NGM/EE and LNG/EE treatment, respectively), and the NPB fraction of LNG (0.7%) during NGM/EE treatment was lower (p < 0.001) than during LNG/EE treatment (1.4%). Combining these serum distributions with the Cmax and AUC0–24h data obtained after NGM/EE treatment gave NPB and albumin-bound values of NGMN that were much greater than the corresponding LNG values. Furthermore, the Cmax and AUC0–24h values for NPB LNG during NGM/EE treatment were estimated to be lower than during LNG/EE treatment. Since LNG is primarily bound by SHBG, its access to target tissues is restricted. Moreover, because SHBG does not bind NGMN, it appears to be quantitatively the more important NGM metabolite available to target tissues, and probably accounts for a substantial proportion of the progestogenic activity of NGM/EE OCs. However, it is also possible that simultaneous exposure of NGMN and LNG after treatment with NGM/EE may provide clinical benefits not seen with LNG/EE combinations. [Copyright &y& Elsevier]

Human breast cancer tissue contains enzymes (estrone sulfatase, 17β-hydroxysteroid dehydrogenase, aromatase) involved in the last steps of estradiol (E2) formation. In this tissue, E2 can be synthesized by two main pathways: (1) sulfatase—transforms estrogen sulfates into bioactive E2, and the (2) aromatase—converts androgens into estrogens. Quantitative assessment of E2 formation in human breast tumors indicates that metabolism of estrone sulfate (E1S) via the sulfatase pathway produces 100–500 times more E2 than androgen aromatization.In the present study, we demonstrated in T-47D and MCF-7 human breast cancer cells that norelgestromin (NGMN) (a metabolite of norgestimate) is a potent inhibitory agent of the estrone sulfatase activity. After 24 h incubation of physiological concentrations of E1S (5×10−9 mol/l) the inhibitory effect of NGMN at concentrations of 5×10−9, 5×10−7 and 5×10−5 mol/l was 43±7, 74±4 and 97±2%, respectively, in T-47D cells; 25±4, 57±5 and 96±2% respectively, in MCF-7 cells. Comparative studies using medroxyprogesterone acetate (MPA) showed that this progestin also has an inhibitory effect on sulfatase activity, but significantly less intense than that of NGMN. The inhibition for MPA at concentrations of 5×10−9, 5×10−7 and 5×10−5 mol/l was 31±5, 47±3 and 61±3%, respectively, for T-47D cells; 6±3, 20±3 and 63±4%, respectively, for MCF-7 cells.In conclusion, the present data show that NGMN is a very potent inhibitory agent for sulfatase activity in the hormone-dependent breast cancer cells, resulting in decreased tissue concentration of E2. The clinical significance of this finding remains to be elucidated. [Copyright &y& Elsevier]

Aims To determine the pharmacokinetic profile of norelgestromin (NGMN) and ethinyloestradiol (EE) following application of the contraceptive patch, Evra™ / Ortho Evra™ , at each of four anatomic sites (abdomen, buttock, arm, and torso). Methods Thirty-seven healthy, nonpregnant women aged 20–45 years participated in this open-label, four-period crossover study. Subjects were randomized to one of four treatment (site of application) sequences. Each patch was worn for 7 days, with a 1 month washout between treatments. Blood samples were collected before and at various times up to 240 h after application of each patch. Serum samples were assayed for NGMN and EE by validated methods. Results The serum concentration reference ranges for NGMN and EE are 0.6–1.2 ng ml-1 and 25–75 pg ml-1 , respectively, based on studies of the mean C ave of oral norgestimate 250 µg and EE 35 µg. For all application sites, mean concentrations of NGMN and EE remained within these ranges during the 7 day wear period. Absorption of NGMN and EE during patch application on the buttock, arm, and torso was equivalent. Absorption of NGMN and EE during patch application on the abdomen was approximately 20% less than observed for the other three sites, although mean serum concentrations were still within reference ranges. A previous study demonstrated therapeutic equivalence of patches worn on the abdomen vs other sites. Conclusions Serum concentrations of NGMN and EE from the contraceptive patch remain within the reference ranges throughout the 7 day wear period, regardless of the site of application (abdomen, buttock, arm, or torso). [ABSTRACT FROM AUTHOR]