Effects of transdermal and oral contraceptives on estrogen-sensitive hepatic proteins

OBJECTIVE: The purpose of this study was to evaluate the effects of the contraceptive patch and an oral contraceptive (OC) on serum concentrations of estrogen-sensitive hepatic proteins, ethinyl estradiol (EE) and levonorgestrel (LNG). METHODS: Twenty-four women were randomized to receive three cycles of a contraceptive patch that delivers EE 20 microg/day and norelgestromin 150 microg/day or an OC that contains EE 35 microg and norgestimate 250 microg. Blood samples were taken at baseline and at the end of Cycle 3. Serum levels of sex-hormone-binding globulin (SHBG), thyroxine-binding globulin (TBG), corticosteroid-binding globulin (CBG) and C-reactive protein (CRP) were quantified by immunoassay methods. EE and LNG levels in patch users were measured by radioimmunoassay (RIA) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. The paired t test and Student's t test were used for statistical analysis. RESULTS: Nineteen women completed the study (patch, n=10; OC, n=9). Treatment with both the patch and OC resulted in significant increases from baseline in SHBG, TBG and CBG. The increase in CRP was significant in the patch group and approached significance in the OC group. The increases in SHBG and TBG observed with the patch were significantly greater than those associated with the OC. By way of RIA and LC-MS/MS assay methods, the patch was associated with mean EE levels of 114 and 111 pg/mL, respectively. CONCLUSIONS: The serum concentrations of estrogen-sensitive hepatic proteins and EE associated with the patch suggest that this new contraceptive system may have relatively large net estrogen effects.     

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.     

Effect of low-dose oral contraceptives on androgenic markers and acne

Oral contraceptives (OC) suppress excess androgen production; however, different progestins in combination with low-dose estrogens produce divergent effects on sex hormone-binding globulin (SHBG) and testosterone that may influence clinical outcomes. This multicenter, open-label, randomized study compared biochemical androgen profiles and clinical outcomes associated with two OC containing the same amounts of ethinyl estradiol (EE, 20 micrograms) but different progestins, levonorgestrel (LNG, 100 micrograms), and norethindrone acetate (NETA, 1000 micrograms). Fifty-eight healthy women (18-28 years old) received three cycles of treatment with LNG/EE (n = 30) or NETA/EE (n = 28). The results showed that LNG reduced androgen levels in three compartments--adrenal, ovarian, and peripheral. NETA reduced only adrenal and peripheral androgens. Despite a 2.2-fold greater relative increase in SHBG with NETA than LNG, bioavailable testosterone (T) was reduced by the same amount with LNG and NETA. Both treatments improved acne and were well tolerated. Low-dose OC (EE, 20 micrograms) are effective in reducing circulating androgens and acne lesions without causing weight gain. Although LNG and NETA affected secondary markers differently, both OC formulations produced an equivalent decrease in bioavailable.     

Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone

ObjectivesTo evaluate the effect on endocrine and metabolic parameters of a new combined oral contraceptive (COC) containing estetrol (E4) and drospirenone (DRSP).Study designRandomized, open-label, controlled, 3-arm, parallel study. Healthy subjects received either E4 15 mg/DRSP 3 mg (E4/DRSP) (n = 38), or ethinylestradiol (EE) 30 µg/levonorgestrel (LNG) 150 µg (n = 29), or EE 20 µg/DRSP 3 mg (n = 31) for 6 treatment cycles. Median percentage change from baseline to cycle 3 and to cycle 6 were evaluated for endocrine parameters, liver proteins, lipid profile, and carbohydrate metabolism.ResultsAt cycle 6, E4/DRSP treatment had less effect on gonadotropins (follicle stimulating hormone [FSH] +30.5%, luteinizing hormone [LH] ?7.5%) compared to EE/LNG (FSH ?84.0%, LH ?92.0%) and EE/DRSP (FSH ?64.0%, LH ?90.0%). With E4/DRSP increases in total cortisol (+26.0%) and cortisol binding globulin ([CBG] (+40.0%) were less compared to EE/LNG (cortisol +109.0%, CBG +152.0%) and EE/DRSP (cortisol +107.0%, CBG +140.0%). Liver proteins, except CRP, increased, but the effect was less pronounced with E4/DRSP for angiotensinogen (+75.0%) compared to EE/LNG (+170.0%) and EE/DRSP (+206.5%) and for sex hormone binding globulin ([SHBG] +55.0%), compared to EE/LNG (+74.0%) and EE/DRSP (+251.0%). E4/DRSP had minimal impact on lipid parameters; the largest effect was observed for triglycerides (+24.0%), which was less compared to EE/LNG (+28.0%) and EE/DRSP (+65.5%). E4/DRSP had no effect on carbohydrate metabolism.ConclusionsE4/DRSP treatment has limited effects on endocrine and metabolic parameters. The effects on gonadotropins, cortisol, CBG, angiotensinogen, SHBG and triglycerides were less pronounced compared to EE-containing products.Implications statementCombining E4 15 mg with DRSP 3 mg resulted in a COC with a different metabolic profile in comparison to EE-containing products. The clinical relevance of these findings needs to be further assessed, using clinical endpoints to establish the safety profile of this new COC.     

Effect of some oral contraceptives on serum concentrations of sex hormone binding globulin and ceruloplasmin

Serum SHBG and ceruloplasmin (CP) concentrations were measured in women throughout a cycle of treatment with four oral contraceptives. In women receiving 150 micrograms levonorgestrel (LNG) daily both SHBG and CP decreased. SHBG also decreased, but CP increased, in women receiving ethynyloestradiol (EE) 30 micrograms with LNG 150 micrograms. In women taking 35 micrograms EE with either 600 micrograms or 1000 micrograms norethisterone, increases in CP were similar but SHBG increased more with the lower dose. Serum concentrations had not returned to pretreatment levels by eight days after cessation of dosing. The findings are compared with similar results for women taking 30 micrograms or 50 micrograms EE or an EE,LNG triphasic formulation. Serum concentrations of the gestagens were also measured. Increases in these concentrations when the gestagen was administered with EE to levels higher than expected from administration of the gestagen alone cannot be explained by increased binding to SHBG but are more likely to be due to changes in their metabolism. Differences in the responses of ostensibly closely related proteins of hepatic origin such as SHBG and CP to the oral contraceptives demonstrate that neither can be extrapolated to other pharmacodynamic responses.     

Pharmacokinetics of levonorgestrel and ethinylestradiol in 9 women who received a low-dose oral contraceptive over a treatment period of 3 months and, after a wash-out phase, a single oral administration of the same contraceptive formulation.

The pharmacokinetics of levonorgestrel (LNG) and ethinylestradiol (EE2) were determined in 9 healthy women (age 23 to 42 years), during a treatment period of three months with a low-dose oral contraceptive, containing 0.15 mg LNG together with 0.03 mg EE2 (Microgynon). After a wash-out period of 3 months, 8 of these women received a single administration of the same formulation. The results showed that there was an increase in serum trough levels of LNG, reaching steady-state in the second half of each treatment cycle. The LNG levels achieved were about 3 to 4 times higher than anticipated on the basis of single dose administration. At the end of treatment cycles one and three, the terminal half-life of LNG was in the range of 24-26 h, while a mean value of 20 h was observed following single dose administration. An EE2-induced increase in the SHBG concentration of about 50% as compared to pretreatment values was observed during a treatment cycle. Pretreatment values were reached following the drug-free interval of 7 days between two cycles. After single dose administration, the free fraction of LNG was 1.3 +/- 0.2% and the fractions bound to SHBG and albumin were 64.1 +/- 4.2% and 34.6 +/- 4.0%, respectively. Serum protein binding of LNG did not change during chronic treatment. An about 50% reduction in total and unbound clearance of LNG was observed during chronic treatment, as compared to single dose administration. Increased SHBG binding capacity and a reduced hepatic metabolic capacity were discussed as possible causes of accumulating LNG concentrations in the serum. On the last day of treatment cycles one and three, the AUC(0-24h) values of EE2 were 728 +/- 314 and 778 +/- 318 pg x ml-1 x h, respectively, and were in keeping with data reported from others.     

Effect of four different oral contraceptives on various sex hormones and serum-binding globulins

In a double-blind, controlled, randomized, four-arm, bicentric clinical study, the effect of four oral contraceptives (OCs) on various hormone parameters and serum-binding globulins was investigated. Four groups with 25 volunteers each (18-35 years of age) were treated for six cycles with monophasic combinations containing 21 tablets with either 30 microg ethinylestradiol (EE) + 2 mg dienogest (DNG) (30EE/DNG), 20 microg EE + 2 mg DNG (20EE/DNG), 10 microg EE + 2 mg estradiol valerate (EV) + 2 mg DNG (EE/EV/DNG) or 20 microg EE + 100 microg levonorgestrel (LNG) (EE/LNG). The study was completed by 91 subjects. Blood samples were taken after at least 12 h of fasting on Day 21-26 of the preceding control cycle and on Day 18-21 of the first, third and sixth treatment cycle. The serum concentrations of free testosterone were significantly decreased by about 40-60% in all four groups, while those of dehydroepiandrosterone sulfate (DHEAS) showed a time-dependent decrease during treatment. Except for EE/EV/DNG, which increased prolactin significantly during the third and sixth cycles, no change was observed with the EE-containing preparations. There was a significant increase in the levels of serum-binding globulins during treatment, which differed according to the composition of the OCs used. The rise in sex hormone-binding globulin (SHBG) was highest during intake of 30EE/DNG (+320%) and lowest with EE/LNG (+80%), while the effect of 20EE/DNG and EE/EV/DNG was similar (+270%). The thyroxine-binding globulin (TBG) levels increased significantly, by 50-60%, during treatment with the DNG-containing formulations, while the effect of EE/LNG was less significant (+30%). The rise in corticosteroid-binding globulin (CBG), which occurred in all groups, was most pronounced in women treated with 30EE/DNG (+90%) and least with EE/EV/DNG (+55%), indicating a strong influence of EE and no effect of the progestogen component. In all treatment groups, the frequency of intracyclic bleeding rose in the first treatment cycle and decreased thereafter. Cycle control was significantly better with 30EE/DNG or EE/LNG than with 20EE/DNG or EE/EV/DNG. There was no significant change in blood pressure, body mass index or pulse rate throughout the study. In conclusion, the DNG-containing OCs caused a higher rise in SHBG and TBG levels than the LNG-containing preparation. The effects on CBG suggest a lesser hepatic effect of 2 mg EV as compared to 20 or 30 microg EE. In contrast to EE, the use of estradiol in OCs appeared to increase prolactin release, while the cycle control was better with the OC containing 30 microg EE.     

Matched-pairs analysis of ovarian suppression during oral vs. vaginal hormonal contraceptive use

Background

This study was conducted to compare ovarian suppression during oral vs. vaginal hormonal contraceptive use. Secondary aims included comparison of endometrial thickness and bleeding patterns.

Methods

In two open-label trials assessing ovarian suppression, 33 compliant women completed both studies. They first used oral contraceptive pills (OCs) [randomized to either 20 mcg ethinyl estradiol (EE)/100 mcg levonorgestrel (LNG) or 30 mcg EE/150 mcg LNG] and subsequently used contraceptive vaginal rings (CVRs) (daily release of 15 mcg EE/120 mcg etonogestrel), all 21/7-day regimens. Participants had at least one run-in cycle using each contraceptive method prior to evaluation. During one cycle of each method, women underwent biweekly transvaginal sonography to measure ovarian follicular diameters and endometrial thickness. We also noted presence of a corpus luteum or a ruptured follicle as a marker of ovulation. Participants recorded bleeding days on paper calendars. We used matched-pairs analyses as appropriate.

Results

During follow-up, we identified at least one ovarian follicle ≥8 mm in 20/33 (61%) OC users and 12/33 (36%) CVR users (matched-pairs analysis, p=.02). Similar trends were seen for larger follicles; however, we had limited statistical power to evaluate these differences. Median follicular diameter among OC users was larger than median follicular diameter among CVR users (p=.01). We did not observe a corpus luteum or ruptured follicle in any participant during either study. Endometrial thickness was similar during OC and CVR use (mean 4.1±1.4 vs. 4.1±1.6 mm, p=.9), as was the number of bleeding or spotting days (mean 2.1±2.4 vs. 1.9±2.1, p=.8). Oral contraceptive pill dose was unrelated to follicle diameter, endometrial thickness or bleeding.

Conclusions

Ovarian follicles ≥8 mm were more common in 33 compliant women during OC use than during CVR use, indicating that CVR use results in greater ovarian suppression than OC use.     

Effects of concurrent vaginal miconazole treatment on the absorption and exposure of Nestorone® (segesterone acetate) and ethinyl estradiol delivered from a contraceptive vaginal ring: a randomized,crossover drug–drug interaction study

Objectives

To evaluate the effects of concurrent administration of three vaginal miconazole nitrate formulations on the absorption and exposure of Nestorone® (segesterone acetate) and ethinyl estradiol from a novel contraceptive vaginal ring (NES/EE CVR).

Endometrial effects of a 91-day extended-regimen oral contraceptive with low-dose estrogen in place of placebo

BACKGROUND: The study was conducted to evaluate the effects of a 91-day extended-regimen oral contraceptive (OC) containing levonorgestrel (LNG) with low-dose ethinyl estradiol (EE) in place of placebo on endometrial histology. STUDY DESIGN: Endometrial biopsies were obtained prior to initiation and posttreatment, between cycle Days 60 and 84 (during combination EE/LNG tablets), between cycle Days 85 and 91 (during low-dose EE tablets) or after completion of therapy. RESULTS: Paired endometrial biopsy samples obtained before and after treatment were available for 63 subjects. Biopsy results demonstrated that this OC regimen did not promote unexpected changes in the endometrium, either during the course of active treatment with EE/LNG or during the 7-day low-dose EE interval. Endometrial hyperplasia or malignancy was not observed in any endometrial biopsy sample. CONCLUSION: Use of a 91-day extended-regimen OC with low-dose EE in place of placebo was not associated with any untoward effects on the endometrium.     

Continuous,daily levonorgestrel/ethinyl estradiol vs. 21-day,cyclic levonorgestrel/ethinyl estradiol: efficacy,safety and bleeding in a randomized,open-label trial

BackgroundThis Phase 3, randomized, open-label, multicenter study conducted at 44 sites in Europe evaluated the safety and efficacy of a continuous, daily regimen of levonorgestrel (LNG) 90 mcg/ethinyl estradiol (EE) 20 mcg compared with a 21-day, cyclic LNG 100 mcg/EE 20 mcg regimen.Study DesignThree hundred twenty-three healthy women were randomized to continuous LNG 90 mcg/EE 20 mcg and 318 subjects to cyclic LNG 100 mcg/EE 20 mcg for 1 year (13 pill packs). Pearl index, adverse event (AE) incidence and bleeding profiles were assessed.ResultsNo pregnancies occurred with the continuous oral contraceptive (OC) (Pearl index=0.00). As the study progressed, the percentage of women who achieved amenorrhea during each 28-day pill pack increased: 40% at pill pack 7, 53% at pill pack 13. The percentage of women with no bleeding [with or without spotting (defined as not requiring sanitary protection)] was 50%, 69% and 79% at pill packs 3, 7 and 13, respectively. The incidence of AEs was similar to that of the cyclic OC (except for metrorrhagia and vaginal bleeding in the first 6 months).ConclusionsContinuous LNG 90 mcg/EE 20 mcg was shown to be a safe and effective OC in this direct comparison to a cyclic OC. Suppression of menses and the potential for no bleeding requiring sanitary protection may be provided by this continuous, low-dose OC.     

Bleeding pattern and cycle control with an estradiol-based oral contraceptive: a seven-cycle, randomized comparative trial of estradiol valerate/dienogest and ethinyl estradiol/levonorgestrel

Background

This study compared the bleeding pattern, cycle control and safety of an oral contraceptive (OC) comprising estradiol valerate/dienogest (E2V/DNG; administered using a dynamic dosing regimen) with a monophasic OC containing ethinyl estradiol 20 mcg/levonorgestrel 100 mcg (EE/LNG). E2V releases estradiol (E2), which is identical to endogenously produced 17β-estradiol.

Study design

This was a randomized, multicenter, double-blind, double-dummy trial lasting seven cycles in healthy women aged 18-50 years.

Results

Overall, 798 women were randomized and received allocated treatment (399 per group). There were significantly fewer bleeding/spotting days reported by women who received E2V/DNG than those who received EE/LNG [17.3±10.4 vs. 21.5±8.6, respectively, p<.0001, Reference Period 1 (Days 1-90); and 13.4±9.vs. 15.9±7.1, respectively, p<.0001, Reference Period 2 (Days 91-180)]. Through Cycles 1-7, the occurrence of scheduled withdrawal bleeding per cycle was 77.7-83.2% with E2V/DNG and 89.5-93.8% with EE/LNG (p<.0001 per cycle). The duration and intensity of scheduled withdrawal bleeding were reduced with E2V/DNG vs. EE/LNG. The incidence of intracyclic bleeding was similar with E2V/DNG (10.5%-18.6%) and EE/LNG (9.9%-17.1%) (p>.05 per cycle). No unintended pregnancies occurred with E2V/DNG, but there was one unintended pregnancy with EE/LNG. Adverse drug reactions occurred in 10.0% and 8.5% of women taking E2V/DNG and EE/LNG, respectively. Overall, 79.4% of women were satisfied with E2V/DNG and 79.9% with EE/LNG.

Conclusions

A novel OC composed of E2V/DNG is associated with an acceptable bleeding profile that is comparable to that of an EE-containing OC.     

A multicenter,randomized study of an extended cycle oral contraceptive

OBJECTIVE: To assess the efficacy and safety of Seasonale, 91-day extended cycle oral contraceptive (OC). METHODS: A parallel, randomized, multicenter open-label, 1-year study of the OC Seasonale [30 microg ethinyl estradiol (EE)/150 microg levonorgestrel (LNG), and Nordette-28 (30 microg EE/150 microg LNG)] in sexually active, adult women (18-40 years) of childbearing potential. Patients received either four 91-day cycles of extended cycle regimen OC, or 13 cycles of the conventional 28-day OC with daily monitoring of compliance and bleeding via electronic diaries. RESULTS: When taken daily for 84 days followed by 7 days of placebo, the extended cycle regimen was effective in preventing pregnancy and had a safety profile that was comparable to that observed with the 28-day OC regimen that served as the control. While unscheduled (breakthrough) bleeding was reported among patients treated with the extended cycle regimen, it decreased with each successive cycle of therapy and was comparable to that reported by patients who received the conventional OC regimen by the fourth extended cycle. CONCLUSION: This study demonstrated that Seasonale, 91-day extended cycle OC containing 84 days of 30 microg EE/150 microg LNG followed by 7 days of placebo, was effective, safe and well tolerated.     

Continuous, daily levonorgestrel/ethinyl estradiol vs. 21-day, cyclic levonorgestrel/ethinyl estradiol: efficacy, safety and bleeding in a randomized, open-label trial

Background

This Phase 3, randomized, open-label, multicenter study conducted at 44 sites in Europe evaluated the safety and efficacy of a continuous, daily regimen of levonorgestrel (LNG) 90 mcg/ethinyl estradiol (EE) 20 mcg compared with a 21-day, cyclic LNG 100 mcg/EE 20 mcg regimen.

Study Design

Three hundred twenty-three healthy women were randomized to continuous LNG 90 mcg/EE 20 mcg and 318 subjects to cyclic LNG 100 mcg/EE 20 mcg for 1 year (13 pill packs). Pearl index, adverse event (AE) incidence and bleeding profiles were assessed.

Results

No pregnancies occurred with the continuous oral contraceptive (OC) (Pearl index=0.00). As the study progressed, the percentage of women who achieved amenorrhea during each 28-day pill pack increased: 40% at pill pack 7, 53% at pill pack 13. The percentage of women with no bleeding [with or without spotting (defined as not requiring sanitary protection)] was 50%, 69% and 79% at pill packs 3, 7 and 13, respectively. The incidence of AEs was similar to that of the cyclic OC (except for metrorrhagia and vaginal bleeding in the first 6 months).

Conclusions

Continuous LNG 90 mcg/EE 20 mcg was shown to be a safe and effective OC in this direct comparison to a cyclic OC. Suppression of menses and the potential for no bleeding requiring sanitary protection may be provided by this continuous, low-dose OC.     

Multicenter, comparative study of cycle control, efficacy and tolerability of two low-dose oral contraceptives containing 20 microg ethinylestradiol/100 microg levonorgestrel and 20 microg ethinylestradiol/500 microg norethisterone

A comparison of cycle control, efficacy and tolerability of two oral contraceptive preparations containing 20 microg ethinylestradiol combined with either 100 microg levonorgestrel (EE/LNG 20/100) or 500 microg norethisterone (EE/NET 20/500) was conducted. These results were compared to a standard reference preparation, containing 30 microg ethinylestradiol combined with 150 microg levonorgestrel (EE/LNG 30/150). Efficacy data from 8,544 treatment cycles were obtained from 767 women. Good cycle control and effective contraception was achieved with the two LNG preparations, however, the cycle control results were less favorable with EE/NET 20/500. The cumulative incidence of women with at least one episode of intermenstrual bleeding from cycles 2 to 7 (primary target variable) was 43.9% for EE/LNG 20/100, 72.7% for EE/NET 20/500, and 15.7% for the standard EE/LNG 30/150. The difference between the 2 20 microg of EE preparations, which favored EE/LNG 20/100, was statistically significant (p = 0.001). The overall spotting rates (cycles 1-13) were 9.3% for EE/LNG 20/100, 21.7% for EE/NET 20/500, and 3.3% for the standard EE/LNG 30/150. Amenorrhea was reported in 7.1% (EE/LNG 20/100), 20.6% (EE/NET 20/500), and 0.9% (standard EE/LNG 30/150), respectively. Intermenstrual bleeding episodes were shorter with EE/LNG 20/100 and EE/LNG 30/150 of the 13 treatment cycles. The study Pearl indices were 0.9 for EE/LNG 20/100, 1.9 for EE/NET 20/500, and 0.0 for EE/LNG 30/150. All three treatments were well tolerated. However, tolerability was somewhat less favorable with EE/NET 20/500. A total of 160 women prematurely discontinued the study for various reasons (EE/LNG 20/100: 7%; EE/NET 20/500: 18%; EE/LNG 30/150: 4%). The overall adverse event incidence rate during the trial was low in all groups. Blood pressure remained largely unaffected. Thirteen serious adverse events were recorded for all treatment groups, all but one were assessed as not related to the treatments. There were no remarkable treatment related differences in mean body weight throughout the study and the laboratory values were largely unaffected in all three treatments groups.     

Evaluation of pituitary-ovarian axis suppression with three oral contraceptive regimens

BACKGROUND: The study was conducted to evaluate follicular development and hormone patterns with three oral contraceptive (OC) regimens before, during and after the 7-day hormone-free interval (HFI) or 7-day ethinyl estradiol (EE)-supplemented interval. STUDY DESIGN: The study is a single-center, open-label, prospective, randomized trial to evaluate pituitary-ovarian suppression with three OC regimens containing identical hormones: 30 mcg of EE and 150 mcg of levonorgestrel (LNG). METHODS: After a standard 21/7 OC baseline cycle, subjects were randomized to one of three treatment groups: (1) three 21/7-day cycles of 150 mcg LNG/30 mcg EE for 21 days followed by 7 days of placebo (n=10); (2) one 84/7-day cycle of 150 mcg LNG/30 mcg EE for 84 days followed by 7 days of placebo (n=12) and (3) one 84/7EE-day cycle of 150 mcg LNG/30 mcg EE for 84 days followed by 7 days of 10 mcg EE (n=11). Estradiol; follicle-stimulating hormone (FSH); luteinizing hormone and inhibin-B levels, ovarian follicles and daily symptom diaries were collected. RESULTS: Compared to subjects receiving placebo during the 7-day HFI, those receiving EE demonstrated reductions (p<.05) in both FSH and estradiol. Number of developing follicles was less after the 7-day EE interval compared to that after 7-day HFI. Subjects on the 84/7 and 84/7EE regimens reported less (p=.03) daily menstrual flow than those on the 21/7-day regimen. A trend (p=.06) toward reduced headaches during the 7-day EE-supplemented interval was noted. CONCLUSIONS: Supplementation of the standard 7-day HFI with 10 mcg EE after 84 days of an extended OC decreased FSH levels and decreased the number of developing follicles.     

Evaluation of a continuous regimen of levonorgestrel/ethinyl estradiol: phase 3 study results

OBJECTIVE: This study was conducted to evaluate the safety and efficacy of a continuous daily regimen of levonorgestrel (LNG) 90 microg/ethinyl estradiol (EE) 20 microg (continuous LNG/EE). METHODS: Healthy women aged 18-49 years with regular menstrual cycles for 3 months enrolled in this single-treatment open-label study and took one pill of LNG 90 microg/EE 20 microg daily for 12 months. RESULTS: For the 2134 subjects enrolled, the Pearl Index method failure was 1.26, and user failure was 0.34. While on Pill Pack 13, 58.7% of subjects reported amenorrhea and 79.0% reported absence of bleeding. Overall, the number of bleeding and spotting days per pill pack declined progressively. Adverse events and discontinuations were comparable to those reported for cyclic oral contraceptive (OC) regimens, except for higher rates in those related to uterine bleeding. CONCLUSIONS: Continuous LNG/EE demonstrated a good safety profile and efficacy similar to cyclic OCs. The regimen continuously inhibited menses, increased the incidence of amenorrhea over time and, except for a subset of women, decreased the number of bleeding and spotting days.     

Cycle control with oral contraceptives containing 20 micrograms of ethinyl estradiol. A multicenter, randomized comparison of levonorgestrel/ethinyl estradiol (100 micrograms/20 micrograms) and norethindrone/ethinyl estradiol (1000 micrograms/20 micrograms).

A randomized, open-label, multicenter study was undertaken to compare the effects of oral contraceptives (OC) containing 100 micrograms levonorgestrel (LNG)/20 micrograms ethinyl estradiol (EE) (Aless/Loette) and 1000 micrograms norethindrone acetate (NETA)/20 micrograms EE (Loestrin Fe 1/20) on menstrual cycle control over four cycles of use. A total of 84 evaluable women provided 274 cycles of exposure in the LNG/EE group, and 89 women provided 289 cycles of exposure in the NETA/EE group. Overall, the LNG/EE group achieved a consistently higher percentage of normal menstrual cycles as well as a lower rate of intermenstrual bleeding and amenorrhea than the NETA/EE group. In cycle 4, 63.8% of cycles were normal in the LNG/EE group compared with 41.9% in the NETA/EE group (p < 0.005). Of the total cycles in the NETA/EE group, 10% were amenorrheic, compared with 1.1% in the LNG/EE group. The occurrence of bleeding and/or spotting was significantly lower in cycles 2 and 3 in the LNG/EE group (41.7% and 34.8%, respectively) compared with the NETA/EE group (62.3% and 56.3%; p < 0.05). Other cycle variables were generally similar between groups, as was the incidence of adverse events. These results demonstrate that good cycle control was achieved with an OC containing 20 micrograms EE and that 100 micrograms LNG/20 micrograms EE produces better cycle control than 1000 micrograms NETA/20 micrograms EE.     

Serum lipid and lipoprotein changes induced by new oral contraceptives containing ethinylestradiol plus levonorgestrel or desogestrel

Changes in serum lipid and lipoprotein levels were evaluated in a randomized prospective study conducted in matched healthy young women before and after 6 months' use of three oral contraceptives (OCs): Trigynon (preparation A, n = 13), a triphasic OC containing low doses of ethinylestradiol (EE) and levonorgestrel (LNG); Marvelon (preparation B, n = 14), a monophasic OC containing low doses of EE + Desogestrel (DOG, a new progestogen derived from LNG); and Ovidol (preparation C, n = 11), a sequential OC containing higher doses (50 micrograms) of EE + DOG. After 6 months of use, total triglyceride levels were non-significantly increased by preparations A (+ 29% from basal values) and B (+21%), and very significantly increased by preparation C (+90%). Total cholesterol and phospholipids were unchanged by preparations A and B, whereas phospholipids were significantly increased by preparation C. However, HDL-cholesterol, LDL-cholesterol and their epidemiologically important ratios (HDL-chol:total-chol; LDL-chol:HDL-chol) were kept unchanged by all preparations tested. Apolipoprotein A-1 (Apo A-1) was slightly but significantly increased by all three preparations whereas apolipoprotein B (Apo B) was significantly decreased by preparation B. All ratios Apo A-1:Apo B were accordingly ("favorably") increased, especially during treatment with preparation B. In conclusion, the triphasic OC containing low doses of LNG does not induce obvious, clinically significant, alterations of lipid metabolism, and it is also the case for the low-dose monophasic combination of EE + DOG. The higher-dose sequential preparation of EE + DOG behaves as a more estrogenic compound, increasing total triglyceride concentrations above the normal range.     

Short-term variations in bone remodeling markers of an oral contraception formulation containing 3 mg of drospirenone plus 30 microg of ethinyl estradiol: observational study in young postadolescent women

The clinical study of treated subjects and nontreated controls was made in healthy eumenorrheic young postadolescent women volunteers in the Department of Obstetrics and Gynaecology at Cagliari University, to investigate whether an oral contraceptive (OC) containing drospirenone (3 mg) plus ethinyl estradiol (30 microg) (DRSP+EE) can affect bone metabolism. Control group (n = 26) and OC group (n = 28) women did not differ in age, body mass index, waist-to-hip ratio and main outcome measures [urinary levels of deoxypyridinoline and pyridinoline, serum levels of osteocalcin, bone specific alkaline phosphatase (bSAP), total testosterone (total-T), sex hormone-binding globulin (SHBG), progesterone and bone mineral density (BMD) at the heel]. The control group was studied at the luteal phase (LP) during both the first and the sixth menstrual cycle; the OC group was studied during the first cycle at the LP, and on days 16-18 of the sixth cycle of DRSP+EE treatment. At the sixth cycle, in the control group, the main outcome measures did not change compared to baseline. In the OC group, deoxypyridinoline, pyridinoline, osteocalcin, bSAP, total-T and progesterone levels were reduced, whereas SHBG levels were increased. The BMD was unchanged compared to baseline. The results suggest that 6-month DRSP+EE treatment decreases bone turnover.