Conversely, doses of 5 and 10 mg of norethisterone, which are used in the treatment of gynecological disorders, are converted at rates of 0.7% and 1.0% and produce levels of EE that correspond to those produced by 30 and 60 μg dosages of EE, respectively. The levels of EE formed by 0.5 and 1 mg of norethisterone have been estimated based on higher dosages as corresponding to 2 and 10 μg dosages of EE, respectively. At high doses, norethisterone may increase the risk of venous thromboembolism due to metabolism into EE. Neurosteroid activity
Like progesterone and testosterone, norethisterone is metabolized into 3,5-tetrahydro metabolites. Whether these metabolites of norethisterone interact with the GABAA receptor similarly to the 3,5-tetrahydro metabolites of progesterone and testosterone like allopregnanolone and 3α-androstanediol, respectively, is a topic that does not appear to have been studied and hence requires clarification. Steroidogenesis inhibition
Norethisterone is a substrate for and is known to be an inhibitor of 5α-reductase, with 4.4% and 20.1% inhibition at 0.1 and 1 μM, respectively. However, therapeutic concentrations of norethisterone are in the low nanomolar range, so this action may not be clinically relevant at typical dosages.Norethisterone and its major active metabolite 5α-DHNET have been found to act as irreversible aromatase inhibitors (Ki = 1.7 μM and 9.0 μM, respectively). However, like the case of 5α-reductase, the concentrations required are probably too high to be clinically relevant at typical dosages.
Medical uses
Norethisterone is used as a hormonal contraceptive in combination with an estrogen – usually ethinylestradiol (EE) – in combined oral contraceptive pills and alone in progestogen-only pills. Another medical use of norethisterone is to alleviate endometriosis related pain. In fact, 50% of patients who received medical or surgical treatment for endometriosis-related pelvic pain have benefited from progestin therapy. This could be due to the fact that norethisterone induces endometrial proliferation during secretory phase, which has been shown to alleviate endometrial pain complaints. Another way in which norethisterone may be acting to reduce endometrial pain is via inhibition of ovulation. Endometriosis pain and discomfort is worse during ovulation. Contraindications
High-dose (10 mg/day) norethisterone has been associated with hepatic veno-occlusive disease, and because of this adverse effect, norethisterone should not be given to patients undergoing allogeneic bone marrow transplantation, as it has been associated with substantially lower one-year survival post-transplantation. : 217

Side effects
At contraceptive and hormone replacement dosages (0.35 to 1 mg/day), norethisterone has essentially progestogenic side effects only. In most clinical studies of norethisterone for contraception or menopausal hormone therapy, the drug has been combined with an estrogen, and for this reason, it is difficult to determine which of the side effects were caused by norethisterone and which of them were caused by estrogen in such research. However, NETE, an intramuscularly administered prodrug of norethisterone which is used as a long-acting contraceptive, is used without an estrogen, and hence can be employed as a surrogate for norethisterone in terms of understanding its effects and tolerability.