This ATC-code G03CA03 includes several different routes of administration; transdermal, peroral and vaginal, and the different routes of administration have different porphyria safety classifications. Local treatment with estradiol, i.e. vaginal tablets and vaginal ring, is probably not porphyrinogenic, while systemic treatment, i.e. per oral tablets and transdermal patches, is considered as possibly porphyrinogenic.

Common adverse reactions of estradiol depend on the route of administration. Common side effects that can be confused with an acute porphyric attack are abdominal pains, nausea and diarrhoea. These side effects may potentially be porphyrinogenic if leading to a decrease in carbohydrate intake. An in vitro study found that estrogens might directly activate ALAS-1 (Du Plessis 2009). In presence of estrogen, the estrogen receptor-alpha (ER-alpha) bound to estrogen receptor elements (ERE) in the ALAS-1 promotor resulting in an elevated transcription of ALAS-1 and thereby causing a subsequent increase in the rate of the entire heme synthesis pathway.

Estrogens are potentially porphyrinogenic; however, hormone replacement therapy containing estradiol has been used uneventfully by 88 postmenopausal women diagnosed with acute porphyria. Postmenopausal women have a lower endogenous hormone level and a reduced risk of having an acute porphyric attack compared to women of fertile age. The decreased vulnerability after menopause may therefore explain a higher tolerance to estrogen replacement therapy. Local treatment with estradiol, i.e. vaginal ring and vaginal tablets, give a very low plasma concentration and liver exposure. Such administration of the drug is therefore considered as probably not porphyrinogenic. However, we cannot exclude the possibility that systemic estradiol treatment, i.e. peroral tablets and transdermal patches, might elicit an acute attack since the exposure of the liver is higher. One published report describes an acute attack in a postmenopausal woman diagnosed with AIP when using a transdermal patch containing estradiol. These forms of administration are therefore classified as possibly porphyrinogenic. The transdermal patch is preferred over per oral tablets as the percutaneous route avoids first pass effect in the liver.

Estradiol is a natural steroid hormone.

Estradiol is used as hormone replacement therapy (HRT) for estrogen deficiency symptoms in postmenopausal women. The higher doses might also be used as prevention of osteoporosis in postmenopausal women. There are several routes of administration. Estradiol may be administered as a transdermal patch, a vaginal ring, peroral tablets or vaginal tablets. Half-life of estradiol is approximately 1 hour.

During chronic administration of the 7.5 µg vaginal ring and 10 µg vaginal tablet plasma estradiol levels were increased but did not exceed the normal range for postmenopausale women, which is up to 20 pg/ml (Santen 2015). Transdermal patches releasing 25-100 µg/24 hours, gave a peak estradiol serum concentration of 25–105 pg/ml (SPC). Peroral administration of 2 mg estradiol valerate gave a serum concentration of 141 pg/ml (Cano 1999).

Estradiol is predominantly metabolized in the liver to estrone and then to estriol (SPC). CYP1A2 and 3A4 are involved in the hydroxylation of estradiol to estriol, which is further glucuronidated. Estradiol and its metabolites are mainly excreted by the kidneys (SPC). Estradiol is not found to be an inhibitor of CYP2C9, CYP2C19 and CYP3A4, and compared to ethinyl estradiol, it is less likely to cause mechanism-based inhibition due to the lack of an acetylenic group (Laine 2003). Estradiol is listed as an activator of human PXR (Honkakoski 2003, Mnif 2007) and has been found to induce CYP2A6 in vitro (Higasi 2007). However, there are no CYP dependent drug interactions of significance with estradiol as perpetrator (Lexi-interact).

It is from clinical observations well known that progestogens and estrogens have a role in precipitating acute porphyric attacks (Andersson 2003, Bonkovsky 2014, Kauppinen 1992).I n a retrospective population-based study, a total of 48 postmenopausal women diagnosed with AIP had used different forms of HRT containing estradiol for climacteric symptoms without precipitating acute attacks (Andersson 2003). A case report describes acute porphyric attacks in two postmenopausal women diagnosed with AIP when using transdermal patches. One of the women used a patch containing estradiol, while the other used a patch containing estradiol and norethisterone (Wetterberg 1995).

Estradiol has been used uneventfully by 32 patients with acute porphyria. Estriol (a metabolite of estradiol) has been used uneventfully by 8 patients with acute porphyria.