Pharmacodynamics Norethisterone is a potent
progestogen and a weak
androgen and
estrogen. Unlike norethisterone, its major active metabolite
5α-dihydronorethisterone (5α-DHNET), which is formed by transformation via
5α-reductase, has been found to possess both progestogenic and marked
antiprogestogenic activity, although its affinity for the PR is greatly reduced relative to norethisterone at only 25% of that of progesterone.
Androgenic activity Norethisterone has approximately 15% of the affinity of the
anabolic–androgenic steroid (AAS)
metribolone (R-1881) for the AR, and in accordance, is weakly androgenic. Similar findings were observed for
ethisterone (17α-ethynyltestosterone) and its 5α-reduced metabolite, whereas 5α-reduction enhanced both the AR affinity and androgenic potency of
testosterone and
nandrolone (19-nortestosterone) in rodent bioassays. The drug also has estrogenic activity, and estrogens are known to increase SHBG hepatic production and circulating levels, so it would appear that the androgenic activity of norethisterone overpowers its estrogenic activity in this regard. Norethisterone may displace testosterone from SHBG and thereby increase free testosterone levels, and this action may contribute to its weak androgenic effects.
Estrogenic activity (EE), the
metabolite of norethisterone responsible for its
estrogenic activity. Due to these very low relative affinities, it is essentially inactive itself as a
ligand of the ERs at clinical concentrations.
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. However, like the case of 5α-reductase, the concentrations required are probably too high to be clinically relevant at typical dosages. Norethisterone stimulates the
proliferation of
MCF-7 breast cancer cells
in vitro, an action that is independent of the classical PRs and is instead mediated via the
progesterone receptor membrane component-1 (PGRMC1). Certain other progestins act similarly in this assay, whereas
progesterone acts neutrally.
Antigonadotropic effects Due to its progestogenic activity, norethisterone suppresses the
hypothalamic–pituitary–gonadal axis (HPG axis) and hence has
antigonadotropic effects. Due to its antigonadotropic effects, norethisterone suppresses
gonadal
sex hormone production, inhibits
ovulation in women, and suppresses
spermatogenesis in men. The
ovulation-inhibiting dosage of both oral norethisterone and oral norethisterone acetate is about 0.5 mg/day in women. However, some conflicting data exist, suggesting that higher doses might be necessary for full inhibition of ovulation. An intramuscular injection of 200 mg norethisterone enanthate has been found to prevent ovulation and suppress levels of
estradiol,
progesterone,
luteinizing hormone (LH), and
follicle-stimulating hormone (FSH) in women. Early studies of oral norethisterone in men employing doses of 20 to 50 mg/day observed suppression of
17-ketosteroid excretion, increased
estrogen excretion (due to conversion into
ethinylestradiol), suppression of spermatogenesis,
libido, and
erectile function, and incidence of
gynecomastia. A dosage of oral norethisterone of 25 mg/day for 3 weeks in men has been reported to suppress testosterone levels by about 70%, to 100 to 200 ng/dL, within 4 or 5 days, as well as to suppress
sperm count and to have no effect on libido or erectile function over this short time period. In healthy young men, norethisterone acetate alone at a dose of 5 to 10 mg/day orally for 2 weeks suppressed testosterone levels from ~527 ng/dL to ~231 ng/dL (–56%). (5 mg/50 mg) (Mesigyna) in healthy young men. Intramuscular injections of 200 mg norethisterone enanthate once every 3 weeks have also been found to suppress spermatogenesis in men. Similarly, a single intramuscular injection of 50 mg norethisterone enanthate in combination with 5 mg estradiol valerate has been found to strongly suppress testosterone levels in men. Levels of testosterone decreased from ~503 ng/dL at baseline to ~30 ng/dL at the lowest point (–94%) which occurred at day 7 post-injection. A single 2 mg oral dose of norethisterone has been found to result in peak circulating levels of the drug of 12 ng/mL (40 nmol/L), whereas a single 1 mg oral dose of norethisterone in combination with 2 mg estradiol resulted in peak levels of norethisterone of 8.5 ng/mL (29 nmol/L) one-hour post-administration. With the exception of 3α,5α- and 3β,5α-tetrahydronorethisterone, which have significant affinity for the ER and are estrogenic to some degree, the 3,5-tetrahydro metabolites of norethisterone are inactive in terms of affinity for
sex steroid receptors (specifically, the PR, AR, and ER). A small amount of norethisterone is also converted by
aromatase into EE. of norethisterone and its metabolites occurs in spite of
steric hindrance by the
ethynyl group at C17α. ==Chemistry==