A suggested hypothesis for the porphyrinogenic potential of progestins (Thunell 2016) is that they activate the mPRalpha-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-1alpha (Wu 2009). PGC-1alpha may then co-activate FoxO1 and NRF-1, with subsequent induction of the ALAS-1 gene (Handschin 2005).

Progesterone is considered as a potentially porphyrinogenic substance and is 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 this hormone can affect CYP enzymes by induction. Although this effect is described to a limited extent in drug-drug interactions studies in general, it is likely that it has a role in a probable upregulation of the heme biosynthesis.

Progesterone is a steroid hormone.

Progesterone is used in the treatment of dysfunctional uterine bleedings, amenorrhea, for prevention of endometrial hyperplasia caused by conjugated estrogen and as part of assisted reproductive technology treatment. Progesterone may be administered by the oral, intramuscular, subcutaneous, rectal or vaginal route.

Progesterone activate PXR (Kliewer 1998 Honkakoski 2003). Progesterone is not listed as a significant inducer 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. 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).

One report of an attack requiring hospitalisation in a 31 year-old susceptible female with AIP. However there were other factors that could have contributed to the attack. Uneventful use reported in 11 patients with acute porphyria.