A Multi-Center, Open-Label, Pharmacokinetic Drug Interaction Study of Erenumab and a Combined Oral Contraceptive in Healthy Females.

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.

Evaluation of Potential Drug-Drug Interaction Between Delayed-Release Dimethyl Fumarate and a Commonly Used Oral Contraceptive (Norgestimate/Ethinyl Estradiol) in Healthy Women.

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.

The pharmacokinetics of 12-week continuous contraceptive patch use.

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.

UPLC-MS/MS assay for the simultaneous determination of ethinyl estradiol, norgestimate and 17-Desacetyl norgestimate at low pg/mL in human plasma.

Previously, because of the difficulty of measuring very low levels (pg/mL) of norgestimate (NGM) due to rapid metabolism to its active and major metabolite, 17-Desacetyl norgestimate (DNGM), only DNGM and the co-administered ethinyl estradiol (EE2) were required to be analyzed in bioequivalence (BE) studies for oral contraceptive NGM/EE2 tablets. Recently, with more sensitive assays available, health authorities have requested that bioequivalence of NGM be also demonstrated in addition to DNGM and EE2. Therefore, it was important to establish a 3-in-1 method for the quantitation of EE2, NGM and DNGM in human plasma. Here a UPLC-MS/MS method for the simultaneous quantitation of EE2, NGM and DNGM in human plasma at low pg/mL range is described. EE2, NGM, DNGM and their isotopic labeled internal standards (IS) EE2-d4, NGM-d6 and DNGM-d6 in 0.4mL of human plasma were extracted with hexane/ethyl acetate. The extracts were evaporated to dryness and derivatized with dansyl chloride, to enhance the mass spec response. The derivatives were reconstituted with methanol and analyzed by UPLC-MS/MS. In order to minimize the ex-vivo conversion of NGM to DNGM, sodium fluoride/potassium oxalate was used as anti-coagulant. To achieve desirable throughput for sample analysis, UPLC-MS/MS with a run time of 4.4min was utilized. The calibration curve ranges were 5-500pg/mL for EE2 and NGM, and 25-2500pg/mL for DNGM, respectively. The chromatographic separation was achieved on a Waters Acquity UPLC HSS T3 (100×2.1mm, 1.8µm) column with a gradient elution. Assay accuracy, precision, linearity, selectivity, sensitivity and analyte stability covering sample storage and analysis were established. This validated UPLC-MS/MS method has been applied to a BE study for the determination of EE2, NGM and DNGM concentrations in human plasma.

Dolutegravir Has No Effect on the Pharmacokinetics of Oral Contraceptives With Norgestimate and Ethinyl Estradiol.

BACKGROUND: Dolutegravir (DTG; Tivicay; ViiV Healthcare, Research Triangle Park, NC) is an HIV-1-unboosted integrase inhibitor with no cytochrome P450 or uridine 5'diphosphate-glucuronosyltransferase inhibition or induction. As DTG is administered to HIV-1-infected women receiving oral contraceptives, assessing the potential for drug interactions was warranted. OBJECTIVE: To determine the impact of DTG on the pharmacokinetics (PK) and pharmacodynamics (PD) of a common oral contraceptive, norgestimate/ethinyl estradiol (NGM/EE; Ortho-Cyclen; Ortho-McNeil-Janssen Pharmaceuticals, Inc, Raritan, NJ). METHODS: This randomized, 2-period, double-blind, placebo-controlled study was conducted within 1 menstrual cycle at 1 clinical center in the United States; 16 women were enrolled. Participants received NGM 0.25 mg/EE 0.035 mg throughout the study. During days 1 to 10, they were randomized to receive twice-daily DTG 50 mg or matching placebo with food and switched to the other treatment during days 12 to 21. RESULTS: Ratios of area under the concentration-time curve from time 0 until end of the dosage interval (AUC0-τ), maximum plasma concentration, and concentration at the end of the dosage interval of norelgestromin with DTG treatment to the same PK parameters with placebo treatment were 0.975, 0.890, and 0.932, respectively; for EE, ratios were 1.03, 0.99, and 1.02, respectively. No significant differences in luteinizing hormone, follicle-stimulating hormone, and progesterone were detected on days 1, 10, 11, 21, and 22. DTG steady-state AUC0-τ was similar to historical data. No severe or grade 3/4 adverse events occurred. CONCLUSIONS: DTG had no effect on NGM/EE PK or PD. NGM/EE can be administered with DTG without dose adjustment.

Effect of raltegravir on estradiol and norgestimate plasma pharmacokinetics following oral contraceptive administration in healthy women.

AIMS: Oral contraceptives such as norgestimate-ethinyl estradiol (Ortho Tri-Cyclen®) are commonly prescribed in the HIV-infected patient population. A placebo-controlled, randomized, two-period crossover study in healthy HIV-seronegative subjects was conducted to assess the effect of raltegravir on the pharmacokinetics of the estrogen and progestin components of norgestimate-ethinyl estradiol [ethinyl estradiol (EE) and norelgestromin (NGMN), an active metabolite of norgestimate (NGT)]. METHODS: In each of two periods, nineteen healthy women established on norgestimate-ethinyl estradiol contraception (21 days of active contraception; 7 days of placebo) received either 400 mg raltegravir or matching placebo twice daily on days 1-21. Pharmacokinetics were analysed on day 21 of each period. RESULTS: The geometric mean ratio (GMR) and 90% confidence interval (CI) for the EE component of norgestimate-ethinyl estradiol when co-administrated with raltegravir relative to EE alone was 0.98 (0.93-1.04) for the area under the concentration-time curve from 0 to 24 h (AUC(0-24 h) ) and 1.06 (0.98-1.14) for the maximum concentration of drug in the plasma (C(max) ); the GMR (90% CI) for the NGMN component of norgestimate-ethinyl estradiol when co-administered with raltegravir relative to NGMN alone was 1.14 (1.08-1.21) for AUC(0-24 h) and 1.29 (1.23-1.37) for C(max) . There were no discontinuations due to a study drug-related adverse experience, nor any serious clinical or laboratory adverse experience. CONCLUSIONS: Raltegravir has no clinically important effect on EE or NGMN pharmacokinetics. Co-administration of raltegravir and an oral contraceptive containing EE and NGT was generally well tolerated; no dose adjustment is required for oral contraceptives containing EE and NGT when co-administered with raltegravir.

Influence of alitretinoin on the pharmacokinetics of the oral contraceptive ethinyl estradiol/norgestimate.

BACKGROUND: Alitretinoin (9-cis retinoic acid) is currently registered in many European countries and in Canada as the only licensed treatment for severe chronic hand eczema unresponsive to potent topical corticosteroids. Alitretinoin, like all retinoids, is teratogenic, and women of child-bearing potential must strictly adhere to pregnancy-prevention measures. AIM: To investigate the influence of alitretinoin on the pharmacokinetics (PK) of ethinyl estradiol/norgestimate (Ortho Tri-Cyclen 28(®)), a commonly prescribed combination oral contraceptive. METHODS: In total, 16 healthy premenopausal women received three consecutive cycles of the triphasic contraceptive ethinyl estradiol/norgestimate together with concomitant oral alitretinoin 40 mg once daily during cycle 2. Steady-state PK (noncompartmental analysis) of ethinyl estradiol, 17-deacetyl norgestimate, alitretinoin and its main metabolite 4-oxo-alitretinoin were assessed alone and in combination. RESULTS: The PK profiles of ethinyl estradiol and 17-deacetyl norgestimate were similar when contraceptives were given alone or with alitretinoin, and the area under the plasma concentration vs. time curve and the maximum concentration met the conventional criteria for PK equivalence. Similarly, the influence of ethinyl estradiol/norgestimate on systemic exposure to alitretinoin and 4-oxo-alitretinoin was not clinically relevant. Alitretinoin was well tolerated when given either alone or with ethinyl estradiol/norgestimate. CONCLUSIONS: There was no clinically relevant influence of alitretinoin on the PK of ethinyl estradiol/norgestimate, and no influence of ethinyl estradiol/norgestimate on systemic exposure to alitretinoin and 4-oxo-alitretinoin. Consequently, oral contraception with ethinyl estradiol/norgestimate is an appropriate primary method of birth control during alitretinoin treatment for women of childbearing potential.

Determination of norelgestromin in rabbit plasma by LC-MS/MS and its application to the pharmacokinetic study of ORTHO EVRA.

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 0.05-20 ng/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 1.6 ml 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.

Influence of taranabant, an orally active, highly selective, potent cannabinoid-1 receptor (CB1R) inverse agonist, on ethinyl estradiol and norelgestromin plasma pharmacokinetics.

Taranabant, an orally active, potent, and highly selective CB-1 receptor inverse agonist, is being developed for the treatment of obesity. This randomized, placebo-controlled, multiple-dose, crossover study evaluated the effect of taranabant on the pharmacokinetics of ethinyl estradiol and norelgestromin in healthy women receiving > or =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 AUC0-24 h and Cmax of ethinyl estradiol and norelgestromin. Lack of a clinically important effect was declared if the 90% confidence intervals for the geometric mean ratio of AUC0-24 h and Cmax 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 AUC0-24 h and 0.95 (0.88, 1.01) and 0.95 (0.88, 1.01) for Cmax. 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.

Absence of effect of oral rifaximin on the pharmacokinetics of ethinyl estradiol/norgestimate in healthy females.

BACKGROUND: Rifaximin is an oral rifampin analog, and its activity is targeted within the gastrointestinal tract. Some analogs induce the cytochrome P450 family of oxidative enzymes. Ethinyl estradiol (EE), commonly found in oral contraceptives (OCs), is a known CYP3A4 substrate. OBJECTIVE: To determine the potential effect of rifaximin on EE and norgestimate pharmacokinetics. METHODS: In an open-label, crossover study, healthy females received a single dose of OC (EE 0.07 mg/norgestimate 0.50 mg). Following a 1 week washout period, individuals received rifaximin 200 mg every 8 hours for 3 days, with a single dose of OC administered with the ninth rifaximin dose. During both treatment periods, blood samples were collected periodically for up to 96 hours after each OC dose. Plasma concentration-time profiles and pharmacokinetic parameters were characterized for EE and 2 major metabolites of norgestimate, norgestrel (NG) and 17-deacetyl norgestimate (17-DNGM). A drug-drug interaction was confirmed if the 90% CI for the 2 treatment period comparison was outside the 80-125% limit. RESULTS: Twenty-six of 28 women completed the study. No differences in pharmacokinetic parameters were observed for EE, NG, or 17-DNGM when a single dose of the OC was administered alone or with rifaximin. In addition, the 90% CI for the bioavailability contrasts (OC alone vs OC with rifaximin) for the maximum plasma concentration, area under the plasma concentration-time curve from zero to the last measurable plasma concentration or to infinity for EE, NG, and 17-DNGM all ranged from 86-118%. These intervals were within the predefined range for equivalence; therefore, no interaction was observed between OC and rifaximin. Rifaximin was well tolerated. CONCLUSIONS: Administration of a 3 day dosing regimen of oral rifaximin was well tolerated and did not alter the pharmacokinetics of a commonly used combination OC containing EE and norgestimate.

Serum distribution of the major metabolites of norgestimate in relation to its pharmacological properties.

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 >or=3 cycles of oral contraceptive (OC) use. The administration of 250 microg NGM/35 microg 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 microg LNG/30 microg 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 C(max) and AUC(0-24h) 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 C(max) and AUC(0-24h) 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.

Pharmacokinetic overview of Ortho Evra/Evra.

OBJECTIVE: The pharmacokinetics of norelgestromin, the primary active metabolite of norgestimate, plus ethinyl estradiol (EE), delivered by the once-weekly contraceptive patch (Ortho Evra/Evra), have been studied in eight trials. This overview summarizes the relevant pharmacokinetic data for the contraceptive patch. DESIGN: Review article. RESULT(S): The amount of norelgestromin and EE absorbed from the patch is proportional to patch size: the 20-cm(2) patch (Ortho Evra) delivers norelgestromin, 150 microg/d, and EE, 20 microg/d, to the systemic circulation. After single and multiple applications of the contraceptive patch, daily serum concentrations (area under the serum concentration-versus-time curve) of norelgestromin and EE were within the ranges generally seen with oral norgestimate, 250 microg/EE 35 microg (Ortho-Cyclen/Cilest), but without the peaks and troughs characteristic of oral dosing. Moreover, the contraceptive patch maintains serum concentrations of norelgestromin and EE within these ranges for up to 10 days, suggesting that clinical efficacy would be maintained even if a scheduled change is missed for as long as two full days. Regardless of the location of patch application (abdomen, buttock, upper outer arm, or torso [excluding breasts]) and even under conditions of heat, humidity, exercise, and cool-water immersion, efficacious concentrations of norelgestromin and EE are achieved. Coadministration of the patch with tetracycline did not affect the pharmacokinetics of norelgestromin and EE. CONCLUSION(S): The contraceptive patch exhibits an excellent pharmacokinetic profile, maintaining efficacious serum hormone concentrations under varying conditions.

Norgestimate. From the laboratory to three clinical indications.

This review of preclinical studies and clinical trials of efficacy and safety examines the relation between structure and function in the norgestimate (NGM) molecule, describes the pharmacologic characteristics of NGM and evaluates clinical experience with NGM in oral contraception (OC), treatment of hyperandrogenism in women and hormonal replacement therapy (HRT). NGM is a progestin of the 19-norsteroid series with an oxime group on C-3. In women, only low serum levels of NGM can be detected for five hours after ingestion. NGM is swiftly converted into its main metabolite, the 17-deacetylated norgestimate (norelgestromin), which carries the progestogenic properties of NGM. The metabolite reaches a mean peak concentration of 3,500 pg/mL 1.5 hours after intake and has a half-life of > 24 hours. The progestogenic potency of NGM and its main metabolite is comparable to that of progesterone. The doses of NGM in OCs effectively inhibit ovulation and control uterine bleeding. In the triphasic NGM/ethinyl estradiol (EE) OC, the total monthly load of progestin is only 4.5 mg. NGM has a low androgenic impact and does not interfere with the positive metabolic actions of estrogens, notably the estrogen-induced increase in high-density lipoprotein levels. OCs with NGM and EE increase the serum concentration of sex hormone binding globulin threefold, augmenting the binding of circulating testosterone and reducing free testosterone levels by 50%. Consequently, OCs with NGM are therapeutic for hyperandrogenic symptoms, such as acne. In a new type of HRT three-day dosing with 17 beta-estradiol (E2) alone is followed by three-day dosing with E2 plus NGM. This regimen treats vasomotor symptoms, protects the endometrium from hyperproliferation and is associated with a favorable lipid profile. NGM is a versatile progestin suitable for medical use from adolescence through the reproductive years to menopause.

Multiple-dose pharmacokinetics of a contraceptive patch in healthy women participants.

This open-label, randomized study evaluated the pharmacokinetics of norelgestromin (NGMN) and ethinyl estradiol (EE) following the application of a contraceptive patch (1/week) for three cycles (3 weeks/cycle). Healthy women (n = 24) wore a 20-cm(2) patch (ORTHO EVRA/EVRA) on either their abdomen or buttock during blood sampling weeks and on any of four approved sites at other times. Serum was analyzed for NGMN and EE from samples taken during Week 1 of Cycle 1 and Weeks 1-3 of Cycle 3. Steady-state conditions were achieved during the three-cycle study. The patch delivered NGMN and EE at steady-state concentrations within their reference ranges throughout three cycles of treatment; reference ranges are based on studies with ORTHO-CYCLEN/Cilest. Steady-state serum concentrations and area under the curve from 0 to 168 h increased only slightly from Cycle 1, Week 1 to Cycle 3, Week 3 for NGMN and EE, indicating minimal accumulation. Treatment was well tolerated, and patch adhesion was excellent.

Simultaneous quantitative determination of norgestrel and progesterone in human serum by high-performance liquid chromatography-tandem mass spectrometry with atmospheric pressure chemical ionization.

A selective, reliable and rapid method for the simultaneous determination of progesterone and norgestrel concentrations in human serum after taking oral contraceptive tablet has been developed using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS) with atmospheric pressure chemical ionization (APCI) interface. The norethisterone was used as the internal standard. Selected transitions of m/z 313/245 for norgestrel, m/z 315/97 for progesterone and m/z 299/109 for norethisterone were monitored using multiple reaction monitoring (MRM) mode for quantitation. The assay was linear over the concentration range of 0.2-50 ng mL-1 for norgestrel and progesterone. The lower level of quantitation in human serum was obtained at 0.2 ng mL-1 for both norgestrel and progesterone using optimum tuning parameters. The intra-assay precision and inter-assay precision do not exceed 10 and 9%, respectively. The method has been applied to the determination of norgestrel and progesterone in serum of female volunteers.

Determination of norgestimate and its metabolites in human serum using high-performance liquid chromatography with tandem mass spectrometric detection.

A rapid and reliable analytical method is described for the simultaneous determination of a synthetic progestin norgestimate (NGM), and its metabolites, 17-deacetylnorgestimate (17-DA-NGM), 3-ketonorgestimate (3-keto-NGM) and norgestrel (NGL) in human serum using reversed phase high-performance liquid chromatography (HPLC) with tandem mass spectrometric (MS-MS) detection. The assay was linear over the concentration ranges of 0.1-5.0 ng/ml for 17-DA-NGM and NGL and 0.5-5.0 ng/ml for NGM and 3-keto-NGM. The inter-assay reproducibility was consistently less than 10%. The overall recovery of the analytes ranged from 72 to 92%. Serum profiles following oral administration of norgestimate to female volunteers are presented.

Altered reflex control of cutaneous circulation by female sex steroids is independent of prostaglandins.

We tested the hypothesis that the shift in the cutaneous vasodilator response to hyperthermia seen with elevated female reproductive hormones is a prostaglandin-dependent resetting of thermoregulation to higher internal temperatures, similar to that seen in the febrile response to bacterial infection. Using water-perfused suits to control body temperature, we conducted heat stress experiments in resting women under conditions of low and high progesterone and estrogen and repeated these experiments after an acute dose of ibuprofen (800 mg). In six women the hormones were exogenous (oral contraceptives); three women had regular menstrual cycles and were tested in the early follicular and midluteal phases. Resting oral temperature (Tor) was significantly elevated with high hormone status (P < 0.05); this was not affected by ibuprofen treatment (P > 0.2). The Tor threshold for cutaneous vasodilation was significantly increased by high hormone status (+0.27 +/- 0.07 degrees C, P < 0. 02); the shift was not affected by ibuprofen treatment (with ibuprofen: +0.29 +/- 0.08 degrees C, P > 0.2 vs. control experiments). The Tor threshold for sweating was similarly increased by high hormone status (+0.22 +/- 0.05 degrees C, P < 0.05); this shift was not influenced by ibuprofen (with ibuprofen: +0.35 +/- 0. 05, P > 0.1 vs. control experiments). Thus the shift in thermoregulatory control of skin blood flow and sweating mediated by female reproductive steroids is not sensitive to ibuprofen; it therefore appears that this shift is independent of prostaglandins.

Interferencia endometrial de los estrógenos sintéticos en la regulación de la fertilidad / Endometrial interference of synthesis estrogens in fertility regulation

Inicialmente la actividad antiovulatoria de algunos preparados estrógeno/progestacional, era la acción requerida para controlar la fertilidad. A la fecha se ha conseguido una notable reducción en la dosis de ambos componentes hormonales, ofreciendo menos efectos colaterales, con una eficacia anticonceptiva aceptable. Actualmente se dispone de una variedad de esas combinaciones, en donde el estrógeno sintético concentra de 80 a 20 µg/tableta y la prescripción se inicia o el 1er. día o el 5o. día del ciclo menstrual. Al analizar el plasma y el endometrio simultáneamente obtenida de usuarias crónicas que incluían en la tableta dosis de 30 o 50 µg del estrógeno sintético, se observó un perfil de 17B-estradiol como el de la maduración folicular de los ciclos ovulatorios sólo en las mujeres que tomaban la dosis más baja. Sin embargo, este fenómeno de ciclicidad no se obtuvo a nivel local; paralelamente la progesterona circulante en ambos grupos nunca fue > 5.0 ng/ml. La observación indica que se debe buscar un periodo crítico local durante el ciclo menstrual ovulatorio, con mucho menores dosis hormonales para controlar la fertilidad

Comparative progestational activity of norgestimate, levonorgestrel-oxime and levonorgestrel in the rat and binding of these compounds to the progesterone receptor.

The progestational activity of norgestimate (NORG), levonorgestrel-oxime (LNG-oxime) and levonorgestrel (LNG) were compared in a pregnancy maintenance study in rats. The compounds were administered subcutaneously to pregnant rats at several doses, blood samples were collected repeatedly, and the concentration of LNG was measured in these samples. It could be demonstrated that following the administration of NORG and LNG-oxime, LNG was a major metabolite present in the serum. The pharmacological response in rats treated with NORG and LNG-oxime could be related to the systemic exposure of these animals to metabolically derived LNG. Thus, both NORG and LNG-oxime can be regarded as pro-drugs of LNG, the latter being almost exclusively responsible for the pharmacological activity of both pro-drugs. This notion was further supported by studies on the comparative binding affinity of these compounds to rabbit and human progesterone receptor (PR). LNG exhibited the highest binding affinity of the compounds studied. Relative binding affinity (RBA) values of LNG using progesterone as reference (100%) were found to be 125% for rabbit PR (rPR), 143% for human uterine PR (hPR) and 125% for recombinant hPR, respectively. In contrast to LNG, NORG exhibited only a low affinity to the PR, which is documented by RBA values of 1.2% for rPR, 3.2% for uterine hPR and 9% for recombinant hPR. The corresponding values of LNG-oxime were 30% (rPR), 20% (uterine hPR) and 18% (recombinant hPR), respectively. Thus, the combined experimental evidence of the present study does not support the view of NORG being a progestogen on its own as has been suggested by others.