A suggested hypothesis for the porphyrinogenic potential of progestins (Thunell 2016) is that they activate the mPR alpha-PGRMC2 receptor complex (Thomas 2013), which is accompanied by heme binding (Rohe 2009), and may therefore result in a heme drain. A decreased cellular heme pool may then upregulate ALAS-1 (Besur 2014). In addition, the heme-sensing receptor, Rev-erb-alpha, will sense the decreased level of the regulatory heme pool and reduce its repressor effect on PGC-1 alpha (Wu 2009). PGC-1 alpha may then co-activate FoxO1 and NRF-1, with subsequent induction of the ALAS-1 gene (Handschin 2005).

Progestogens are considered as potentially porphyrinogenic substances and are known to have caused porphyric attacks in susceptible carriers of acute porphyria. Both pharmacodynamic and pharmacokinetic properties can explain the triggering effect in acute porphyria. Studies have shown that these hormones can affect CYP enzymes by induction and mechanism-based inhibition. Although these effects are described to a limited extent in drug-drug interactions studies in general, it is likely that they have a role in a probable upregulation of the heme biosynthesis.

Norethisterone (also known as norethindrone) is a 19-nortestosterone derivative.

Progestogen-only oral contraceptive The half-life of norethisterone is 5-12 hours

Norethisterone is mainly metabolized by CYP3A4, with minor contribution from CYP2C19 (Korhonen 2008). Norethisterone is partly metabolised to ethinylestradiol after oral administration of norethisterone or norethisterone acetate in humans. This conversion results in an equivalent dose of about 4-6 µg ethinylestradiol per 1 mg orally administered norethisterone / norethisterone acetate (SPC). Norethisterone has shown weak inhibition of CYP 2C9 In vitro (Korhonen 2008). Norethisterone also possesses an acetylenic group that has been reported to be involved in mechanism-based inhibition (Back 1991). White et. al (1977) reported that norethisterone and ethinyl estradiol caused loss of CYP450 enzymes and an increase in ALAS-1 activity in the liver. However, the study was performed in vitro and in rats and the results cannot be extrapolated to humans. Progesterone and synthetic progestagens activate PXR (Kliewer 1998). Progestogens and estradiol are not listed as significant inducers of CYP 3A4 in most interaction databases (Preissner 2010, NOMA, Lexi-Interact, The Danish Healt and Medicines Authority, Micromedex). Results from clinical studies suggest that the increased hormonal levels in pregnancy have the potential to alter hepatic cytochrome P450 drug metabolism (Anderson 2005). Also, in vitro studies have shown increased CYP mRNA after exposing hepatocytes to progesterone and estradiol levels equal to the high hormonal levels typically seen in the third trimester of pregnancy (Choi 2013). Hormonal therapy generally leads to a much lower plasma concentration relative to the levels of endogenous hormones in pregnancy and may explain the lack of observed significant effects of administered hormones on CYP 3A4 in vivo. However, since progestin have the potential to induce ALAS1 through PXR activation and at the same time cause mechanism-based inhibition of CYP 3A4, this may explain the absence of observed pharmacokinetic drug-drug interactions. For an evaluation of the porphyrinogenicity of these drugs it is important to realize that the inhibitory effect can mask the inductive power and that an increased de novo synthesis of CYP3A4 can take place irrespective of negative results from in vivo DDI-studies. The effects of concomitant induction and inhibition have in general been discussed by Wei et al. for other drugs (Wei 2016). Since CYP3A4 quantitatively is the largest CYP isoenzyme, an increased de novo synthesis of CYP3A4, although masked, will give an upregulation of ALAS-1and thereby a higher flux through the heme biosynthesis. Such a mechanism can possibly in part explain the observed porphyrinogenic effects of these drugs. Studies have shown that women with acute porphyria have an altered 5 alpha-reductase steroid metabolism and it is suggested that this may lead to a diversion from the 5 alpha reductase pathway to formation of 5beta steroid metabolites that may be more potent inductors of ALAS1 (Innala 2012, Anderson 1979, Jacobs 2005).

It is from clinical observations well known that progestogens have a role in precipitating acute porphyric attacks (Andersson 2003, Kauppinen 1992, Bonkovsky 2014).

Uneventful use reported in 3 patients with acute porphyria.