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document
Comparison of the impact of vaginal and oral administration of combined hormonal contraceptives on hepatic proteins sensitive to estrogen . OBJECTIVE We evaluated the effects of a new combined hormonal contraceptive vaginal ring ( CVR ) delivering the nonandrogenic progestin Nestorone ( NES ) and ethinyl estradiol ( EE ) on several key estrogen-sensitive hepatic proteins that may be markers for the risk of arterial or venous disease events and on blood pressure ( BP ) . Because the pharmacologic androgenicity of the progestin in these formulations influences the hepatic impact of EE , we selected an oral contraceptive ( OC ) delivering the androgenic progestin levonorgestrel ( LNG ) and EE as the comparator . We also investigated the effect of delivery route , which is known to modify the hepatic effects of estradiol , but has not been widely studied with EE . STUDY METHODS Women , aged 18-34 years , with no contraindications to the use of combined OCs , were randomized to three cycles of treatment with a CVR delivering NES/EE ( 150/15 microg/day ) or a combined OC providing LNG and EE ( 150/30 microg per tablet ) . Each cycle consisted of 21 days of active treatment , followed by 7 days without treatment . During the last weeks of the pretreatment and third treatment cycles , blood samples were obtained for determinations of plasma concentrations of angiotensinogen , an estrogen-sensitive hepatic protein , and serum concentrations of sex hormone-binding globulin ( SHBG ) , total cholesterol ( TC ) , high-density lipoprotein cholesterol ( HDL-C ) , low-density lipoprotein cholesterol ( LDL-C ) , triglycerides ( TG ) and estrogen- and androgen-sensitive proteins . BP was also measured . RESULTS Of 47 women randomized , 45 completed the study ( CVR : 23 ; OC : 22 ) . Within-group comparisons over time by repeated-measure analysis of variance demonstrated statistically significant changes over time with both treatments for all hepatic proteins ( p < .02 ) but not for TC . The within-group effects , presented as relative percent difference [ 95 % confidence interval ( CI ) ] , were greatest for angiotensinogen [ CVR : 227 % ( 195-262 % ) ; OC : 251.3 % ( 218-288 % ) ] and SHBG [ CVR : 306 % ( 237-389 % ) ; OC : 55 % ( 30-86 ) ] . Both treatments were associated with small changes in systolic BP and diastolic BP ( DBP ) , but only the within-group change in DBP for the OC group was statistically significant ( p = .04 ) . Between-treatment comparisons of third treatment cycle mean values were performed by analysis of covariance ( baseline values as covariate ) . No statistically significant between-treatment differences were found for angiotensinogen , sensitive only to estrogen , or BP . Statistically significant treatment differences were found for all estrogen- and androgen-sensitive proteins ( p < or = .002 ) but not for TC . When presented as relative percent difference between the effects of treatment ( CVR-OC/OC ; 95 % CI of percent difference ) , the difference was largest for SHBG ( 159 % [ 117-210 % ] ) ; smaller relative percent differences were found for HDL-C [ 31.9 % ( 18.5-46.8 % ) ] , LDL-C [ 23.6 % ( 33.4 % to -2.4 % ) ] and TG [ 39.0 % ( 14.0-69.4 % ) ] , but not TC . CONCLUSION Vaginal delivery of a combined hormonal contraceptive did not reduce the EE-associated changes in estrogen-sensitive hepatic proteins observed after use of a combined OC . Significant treatment differences between the NES/EE CVR and the LNG/EE OC were found for SHBG , HDL-C , LDL-C , and TG , proteins sensitive to androgen as well as estrogen . No treatment difference was observed for angiotensinogen , which is sensitive only to estrogen . The observed treatment differences were therefore most likely due to the difference in androgenicity between NES and LNG .
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Intervention_Pharmacological
hormonal contraceptives
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Intervention_Pharmacological
hormonal contraceptive vaginal ring ( CVR )
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Intervention_Pharmacological
nonandrogenic progestin Nestorone ( NES )
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Intervention_Pharmacological
ethinyl estradiol
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Intervention_Pharmacological
CVR
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Intervention_Pharmacological
NES/EE
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Intervention_Pharmacological
LNG
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Intervention_Pharmacological
EE
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Intervention_Pharmacological
NES/EE CVR
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Intervention_Pharmacological
LNG/EE OC
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Outcome_Physical
plasma concentrations of angiotensinogen
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Outcome_Physical
serum concentrations of sex hormone-binding globulin ( SHBG )
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Outcome_Physical
total cholesterol ( TC ) , high-density lipoprotein cholesterol ( HDL-C )
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Outcome_Physical
low-density lipoprotein cholesterol ( LDL-C ) , triglycerides ( TG )
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Outcome_Physical
estrogen- and androgen-sensitive proteins
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Outcome_Physical
BP
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Outcome_Physical
angiotensinogen
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Outcome_Physical
systolic BP and diastolic BP
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Outcome_Physical
DBP
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Outcome_Physical
angiotensinogen
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Outcome_Physical
sensitive only to estrogen
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Outcome_Physical
BP
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Outcome_Physical
estrogen- and androgen-sensitive proteins
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Outcome_Physical
TC .
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Outcome_Physical
SHBG
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Outcome_Physical
HDL-C
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Outcome_Physical
LDL-C
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Outcome_Physical
TG
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Outcome_Physical
EE-associated changes in estrogen-sensitive hepatic proteins
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Participant_Condition
oral contraceptive ( OC )
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Participant_Sex
Women
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Participant_Age
aged 18-34 years
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Participant_Condition
with no contraindications to the use of combined OCs , were randomized to three cycles of treatment with a CVR delivering NES/EE ( 150/15 microg/day ) or a combined OC providing LNG and EE ( 150/30 microg per tablet )
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Participant_Sample-size
47
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Participant_Sex
women
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Participant_Sample-size
45