The goals of this clinical trial are to investigate the effect of the estetrol (E4)-drospirenone combined oral contraceptive (COC) pill on flow-mediated dilatation (FMD) of the brachial artery and pulse wave velocity (PWV), in comparison to the ethinylestradiol (EE)-levonorgestrel COC pill, and to compare their respective effects on blood pressure, chronic inflammatory markers, as well as glycaemic and lipid indices.

The main questions it aims to answer are:

Does E4-drospirenone COC have significantly smaller effects then EE-levonorgestrel COC on FMD, PWV, blood pressure, chronic inflammatory markers, as well as glycemic and lipid indices.

Researchers will compare E4-drospirenone to EE-levonorgestrel to see if the former has lower arterial vascular and metabolic risks.

Participants will:

• be randomised to take E4-drospirenone or EE-levonorgestrel COC pill according to product insert;
• visit the clinic at baseline and 6 and 12 months post-recruitment for checkups and tests

Objectives: (1) To investigate the effect of the estetrol (E4)-drospirenone combined oral contraceptive (COC) pill on flow-mediated dilatation (FMD) of the brachial artery and pulse wave velocity (PWV), in comparison to the ethinyl-estradiol (EE)- levonorgestrel COC pill. (2) To investigate the effect of the E4-drospirenone COC pill on blood pressure, chronic inflammatory markers, as well as glycaemic /lipid indices.

Hypothesis to be tested: E4-drospirenone has non-significant effect on FMD and PWV, as well as on blood pressure, chronic inflammatory markers, glycaemic and lipid profile compared to EE-levonorgestrel.

Design and subjects: Open-label randomised controlled trial. Women (n=98) who are commencing COC pills for contraception or treatment of gynaecological conditions will be recruited.

Study instruments: FMD, carotid-femoral and brachial-ankle PWV, blood pressure, serum high-sensitivity C-reactive protein and interleukin-6 measurements, glycaemic and lipid profile

Interventions: (1) E4 15mg + drospirenone 3mg versus (2) EE 30mcg + levonorgestrel 150mcg

Main outcome measures: FMD, carotid-femoral and brachial-ankle PWV

Data analysis: Data will be analysed with both intention to treat and per protocol approaches. The primary and secondary outcome measures (continuous variables) at baseline and at 6 and 12 months after treatment will be compared by paired t-test (with logarithmic transformation of significantly skewed data). Changes in these parameters will be compared between the two study groups by linear mixed models. P values of <0.05 will be considered statistically significant.

Expected results: E4-drospirenone induces insignificant changes in FMD, PWV as well as blood pressure, chronic inflammatory markers, and glycaemic and lipid profile.

Inclusion Criteria:

• Aged between 18 and 49 years inclusive
• Considering to use the COC pill for contraception or treatment of menstrual disorders

Exclusion Criteria:

• Being diagnosed with menopause
• Having contraindications to COC, including (but not confined to) hypertension, diabetes mellitus with complications, history of ischaemic heart disease, thromboembolism, stroke, severe liver disease, oestrogen-sensitive cancers, undiagnosed abnormal uterine bleeding, smokers aged 35 years or above, or having body mass index >=35 kg/m2
• Planning to get pregnant in the coming 1 year
• Having been pregnant in the past 3 months
• Having been on COC or hormone replacement therapy in the past 3 months (those who had been on these agents can stop these for 3 months as wash-out period before being recruited; this concurs with other similar studies in the literature)
• Having been on anti-hypertensive, anti-diabetic or lipid-lowering agents in the past 3 months
• Refusal to randomization

Cisgender female only

IPD may be shared upon negotiation with reasonable justifications after publication of the results.

After publication of the results.

IPD may be shared upon negotiation with reasonable justifications after publication of the results.