page_title: Ethinylestradiol
section_title: Differences from estradiol
hierarchical_section_title: Ethinylestradiol / Pharmacology / Pharmacodynamics / Differences from estradiol
caption_attribution_description: English: Serum levels of the estrogen-sensitive proteins follicle-stimulating hormone (FSH), sex hormone-binding globulin (SHBG), and pregnancy zone protein (PZP) after 3&#160;months of treatment with 2&#160;mg/day oral estradiol valerate (n = 58), 10&#160;μg/day oral ethinylestradiol (n = 39), or 30&#160;μg/day oral ethinylestradiol (n = 38) in postmenopausal women. Source of the values: &#32;(1986).&#32;"Estrogen induction of liver proteins and high-density lipoprotein cholesterol: comparison between estradiol valerate and ethinyl estradiol". Gynecol. Obstet. Invest.&#32;22&#32;(4): 198–205. DOI:10.1159/000298914. PMID 3817605. Which were reproduced in this secondary source: &#32;(1989).&#32;"Estrogen therapy and liver function--metabolic effects of oral and parenteral administration". Prostate&#32;14&#32;(4): 389–95. DOI:10.1002/pros.2990140410. PMID 2664738.
context_page_description: Ethinylestradiol is an estrogen medication which is used widely in birth control pills in combination with progestins. In the past, EE was widely used for various indications such as the treatment of menopausal symptoms, gynecological disorders, and certain hormone-sensitive cancers. It is usually taken by mouth but is also used as a patch and vaginal ring.
  The general side effects of EE include breast tenderness and enlargement, headache, fluid retention, and nausea among others. In men, EE can additionally cause breast development, feminization in general, hypogonadism, and sexual dysfunction. Rare but serious side effects include blood clots, liver damage, and cancer of the uterus.
  EE is an estrogen, or an agonist of the estrogen receptors, the biological target of estrogens like estradiol. It is a synthetic derivative of estradiol, a natural estrogen, and differs from it in various ways. Compared to estradiol, EE has greatly improved bioavailability when taken by mouth, is more resistant to metabolism, and shows relatively increased effects in certain parts of the body like the liver and uterus.
context_section_description: EE shows strong and disproportionate effects on liver protein synthesis relative to estradiol. The liver as well as the uterus express 17β-hydroxysteroid dehydrogenase (17β-HSD), and this enzyme serves to inactivate estradiol and effectively suppress its potency in these tissues by reversibly converting it into the far less potent estrogen estrone (which has approximately 4% of the estrogenic activity of estradiol). In contrast to estradiol, the 17α-ethynyl group of EE prevents oxidation of the C17β position of EE by 17β-HSD, and for this reason, EE is not inactivated in these tissues and has much stronger relative estrogenic activity in them. This is the mechanism of the disproportionately strong effects of EE on hepatic protein production, which results in a greatly increased magnitude of effect on VTE and cardiovascular risks relative to estradiol.
  On the other hand, due to the loss of inactivation of EE by 17β-HSD in the endometrium (uterus), EE is relatively more active than estradiol in the endometrium and, for this reason, is associated with a significantly lower incidence of vaginal bleeding and spotting in comparison. This is particularly so in the case of combined estrogen and progestogen therapy (as in COCs or menopausal HRT), as progestogens induce the expression of 17β-HSD in the endometrium. The reduced vaginal bleeding and spotting with EE is one of the main reasons that it is used in COCs instead of estradiol, in spite of its potentially inferior safety profile (related to its adverse effects on hepatic protein synthesis and VTE incidence).
  EE has been found to have disproportionate effects on liver protein synthesis and VTE risk regardless of whether the route of administration is oral, transdermal, or vaginal, indicating that the use of parenteral routes over the oral route does not result in EE having proportional hepatic actions relative to non-hepatic actions. However, the potency of EE on liver protein synthesis is in any case reduced with parenteral administration. A dosage of 10 µg/day vaginal EE has been found to be equivalent to 50 µg oral EE in terms of effects on liver protein synthesis, such as stimulation of hepatic SHBG production. As such, parenteral EE, which bypasses the first pass through the liver that occurs with oral EE, has been found to have a 5-fold lower impact on liver protein synthesis by weight than oral EE. In contrast to EE as well as to oral estradiol, transdermal estradiol shows few or no effects on liver protein synthesis at typical menopausal dosages.
caption: Changes in levels of estrogen-sensitive proteins after treatment with oral estradiol or oral ethinylestradiol in postmenopausal women.[52][53] FSH is a pituitary protein and represents general/systemic estrogenic effect, while SHBG and PZP are hepatic proteins and represent liver estrogenic effect.[52][53]
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