Table 4.

Comparison estradiol (E2), ethinylestradiol (EE) and estetrol (E4).

		Estradiol	Ethinylestradiol	Estetrol
Origin		Natural Synthetized in the growing ovarian follicle, corpus luteum, placendal, adrenal and Leydig cells, liver, endometrium, brain muscle and fat tissue	Synthetic derivative	Natural Exclusively synthetized in the fetal liver
Chemical structure
Dosage in COC		20-50 µg	1-3 mg	15 mg
Associated progestogen in COC		NOMAC, DNG	LNG, NETA, NGM, DSG, GSD, DRSP, CPA, DNG, CMA	DRSP
PK profile	Oral bioavailability	Low oral bioavailability but administered either micronized or esterified.	Good oral bioavailability	Good oral bioavailability
	Metabolism	High metabolism into E1 (sulfate) and E3 (sulfate)	High metabolism into various conjugates (glucuronidated, sulfated and hydroxylated metabolites)	No metabolization
	Half-life time	Half-life time around 35 hours (E1 serves as precursor of E2 and can be transformed back into E2)	Half-life time around 12 hours	Half-life time around 28 hours
PD profile			High selectivity for ER (higher affinity for ERα)	High selectivity for ER (higher affinity for ERα); First Native Estrogen with Specific action in Tissues (NEST)
Impact on liver protein synthesis		Minor (non negligeable contribution of E1)	Major	Minor

COC, combined oral contraceptives; CMA, chlormadinone acetate; CPA, cyproterone acetate; DNG, dienogest; DRSP, drospirenone; DSG, desogestrel; ER, estrogen receptor; E1, estrone; E2, estradiol; E3, estriol; GSD, gestodene; LNG, levonorgestrel; NETA, norethisterone acetate; NGM, norgestimate; NOMAC, nomegestrol acetate; PD, pharmacodynamic; PK, pharmacokinetic.