Synthetic vs Natural Estrogen in Combined Oral Contraception

Synthetic vs Natural Estrogen in Combined Oral Contraception- Effect on Insulin Sensitivity, Coagulation, Inflammation and Endometrium - a Comparison With a Progestin-only Preparation.

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02352090

Acronym

SYLVI

Enrollment

Registered

2015-02-02

Start date

2015-04-01

Completion date

2018-12-30

Last updated

2023-06-22

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Contraception

Keywords

Contraception, oral, Ethinyl Estradiol, Estradiol Valerate, Dienogest, Insulin resistance, Chronic inflammation, Coagulation

Brief summary

The main objective of the study is to compare the metabolic effects of natural estradiol and synthetic ethinylestradiol used in combined oral contraception in healthy women. A progestin-only preparation will be used in comparison. The main goal is to study the effects on glucose metabolism, coagulation and a markers of chronic inflammation (such as hs-CRP). Our hypothesis is that the natural estradiol preparation will influence blood glucose levels, markers of coagulation and chronic inflammation less than the ethinylestradiol preparation. The progestin-only preparation will not effect these parameters.

Interventions

DRUGEthinyl estradiol / dienogest

One tablet orally for 9 weeks, continuous use

DRUGEstradiol valerate / dienogest

One tablet orally for 9 weeks, continuous use

DRUGDienogest

One tablet orally for 9 weeks, continuous use

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

OTHER

Masking

NONE

Eligibility

Sex/Gender

FEMALE

Age

18 Years to 35 Years

Healthy volunteers

Yes

Inclusion criteria

* BMI 19-24.9, regular menstrual cycles (21-35 days), a minimum of 2 months without any hormonal contraceptives, no contraindications for use of hormonal contraception

Exclusion criteria

* Polycystic ovaries, hypertension, smoking, alcohol abuse, pregnancy, lactation, abnormal result in pre-screening 2h oral glucose tolerance test, regular medications

Design outcomes

Primary

Measure	Time frame	Description
Matsuda Index- Whole Body Insulin Sensitivity Index	We calculated the change in Matsuda index from baseline to 9 weeks.	Matsuda index is calculated from the standard 2h Oral Glucose Tolerance Test and corresponding insulin values. Matsuda index = 10,000/square root of \[fasting glucose x fasting insulin\] x \[mean glucose x mean insulin during OGTT\]) The Matsuda index is correlated (r = 0.73) with the rate of whole-body glucose disposal during the euglycemic insulin clamp. Matsuda index \<2.5 is considered insulin resistant, higher values indicate less insulin resistance. A decrease in matsuda index over the study period would indicate decreased insulin sensitivity.

Secondary

Measure	Time frame	Description
Fasting Insulin	baseline and 9 weeks	Mean change in fasting serum insulin from baseline to nine weeks
High-sensitivity C Reactive Protein	baseline and 9 weeks	Change in plasma concentrations of acute phase protein 'C reactive protein' (CRP), a marker of chronic inflammation.
Total Cholesterol	baseline and 9 weeks	Change in concentrations of total cholesterol from baseline to nine weeks
Low-Density Lipoprotein (LDL)	baseline and 9 weeks	Change in concentration of Low-Density Lipoprotein LDL from baseline to nine weeks
Triglyceride	baseline and 9 weeks	Change in triglyceride concentrations from baseline to nine weeks
D-dimer	baseline and 9 weeks	Markers of coagulation activation
F1+2	baseline and 9 weeks	Change in plasma concentrations of F1+2 a marker of coagulation activation
Thrombin Generation, ETP Endogenous Thrombin Potential	baseline and 9 weeks	Change from baseline in thrombin generation, measured by thrombin generation assay-Calibrated automated thrombogram
High-Density Lipoprotein (HDL)	baseline and 9 weeks	Change in concentration of High-Density Lipoprotein HDL from baseline to nine weeks

Other

Measure	Time frame	Description
Anti Mullerian Hormone (AMH)	baseline and 9 weeks	Change in Serum concentrations of anti-mullerian hormone reflecting ovarian reserve from baseline to nine weeks

Countries

Finland

Participant flow

Participants by arm

Arm	Count
Synthetic Estrogen + Progestin Ethinyl estradiol / dienogest Ethinyl estradiol / dienogest: One tablet orally for 9 weeks, continuous use	19
Natural Estrogen + Progestin Estradiol valerate / dienogest Estradiol valerate / dienogest: One tablet orally for 9 weeks, continuous use	20
Progestin-Only Dienogest Dienogest: One tablet orally for 9 weeks, continuous use	17
Total	56

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	general malaise	1	0	0
Overall Study	non-specified mild side-effects	0	0	2

Baseline characteristics

Characteristic	Synthetic Estrogen + Progestin	Natural Estrogen + Progestin	Progestin-Only	Total
Age, Continuous	25.8 years STANDARD_DEVIATION 3.8	24.1 years STANDARD_DEVIATION 3.6	24.0 years STANDARD_DEVIATION 3.9	24.6 years STANDARD_DEVIATION 3.8
BMI	23.1 kg/m^2 STANDARD_DEVIATION 1.9	22.4 kg/m^2 STANDARD_DEVIATION 1.6	21.9 kg/m^2 STANDARD_DEVIATION 1.9	22.5 kg/m^2 STANDARD_DEVIATION 1.8
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	0 Participants	0 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	19 Participants	20 Participants	17 Participants	56 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Sex: Female, Male Female	19 Participants	20 Participants	17 Participants	56 Participants
Sex: Female, Male Male	0 Participants	0 Participants	0 Participants	0 Participants
Weight	63.3 kg STANDARD_DEVIATION 4.5	61.4 kg STANDARD_DEVIATION 5.8	58.0 kg STANDARD_DEVIATION 7.1	61.0 kg STANDARD_DEVIATION 6.1

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 19	0 / 20	0 / 17
other Total, other adverse events	0 / 19	0 / 20	0 / 17
serious Total, serious adverse events	0 / 19	0 / 20	0 / 17

Outcome results

Primary

Matsuda Index- Whole Body Insulin Sensitivity Index

Matsuda index is calculated from the standard 2h Oral Glucose Tolerance Test and corresponding insulin values. Matsuda index = 10,000/square root of \[fasting glucose x fasting insulin\] x \[mean glucose x mean insulin during OGTT\]) The Matsuda index is correlated (r = 0.73) with the rate of whole-body glucose disposal during the euglycemic insulin clamp. Matsuda index \<2.5 is considered insulin resistant, higher values indicate less insulin resistance. A decrease in matsuda index over the study period would indicate decreased insulin sensitivity.

Time frame: We calculated the change in Matsuda index from baseline to 9 weeks.

Arm	Measure	Value (MEAN)
Synthetic Estrogen + Progestin	Matsuda Index- Whole Body Insulin Sensitivity Index	-1.02 units on a scale
Natural Estrogen + Progestin	Matsuda Index- Whole Body Insulin Sensitivity Index	-0.10 units on a scale
Progestin-Only	Matsuda Index- Whole Body Insulin Sensitivity Index	-1.45 units on a scale

p-value: 0.27ANOVA

Secondary