Normens Mechanism of Action

Pharmacology: Pharmacodynamics: Norethisterone is a progestogen with negligible androgenic effects. Complete transformation of the endometrium from a proliferative to a secretory state was achieved in estrogenprimed castrated or climacteric women who were administered oral doses of 100-150 mg norethisterone per cycle. The progestogenic effects of norethisterone on the endometrium is the basis of the treatment of dysfunctional bleeding, primary and secondary amenorrhea, and endometriosis with NORMENS. Gonadotropin secretion inhibition and anovulation can be achieved with a daily intake of 0.5 mg of norethisterone. Positive effects of Norethisterone on premenstrual symptoms can be traced back to suppression of ovarian function.
Due to the stabilizing effects of norethisterone on the endometrium, administration of Norethisterone can be used to shift the timing of menstruation. Like progesterone, norethisterone is thermogenic and alters the basal body temperature.
Pharmacokinetics: Absorption: Peak serum concentrations after administration of 5mg NORMENS were 16±5 ng/mL; tmax was 1.5 ±0.6 hours. The bioavailability of a single dose of 1mg norethisterone compared to an equivalent intravenous dose ranged from 47% to 73%, suggesting a significant first pass effect. This study showed that the disposition of norethisterone follows a biexponential pattern with half lives of 0.4-2.6 and 5-13 hours respectively. The apparent volume of disposition was 4.28±0.56L/kg.
Distribution: Norethisterone is bound to serum albumin and to sex hormone binding globulin (SHBG). Only about 3-4 % of the total serum drug concentrations are present as free steroid, about 35% and 61% are bound to SHBG and albumin, respectively. The apparent volume of distribution of norethisterone is 4.4 ± 1.3 L/kg. Following oral administration, the drug serum level time course follows a biphasic pattern. Both phases are characterized by half-lives of 1-2 and about 5-13 hours, respectively. Norethisterone is transferred into milk and the drug levels in breast milk were found to be about 10% of those found in maternal plasma.
Metabolism: Norethisterone is mainly metabolized by saturation of the double bond in ring A and the reduction of the 3-keto group to a hydroxyl group followed by conjugation to the corresponding sulfates and glucuronides. Some of these metabolites are eliminated slowly from plasma, building approximately to a peak at the midpoint of the treatment cycle and rapidly dropping to near baseline levels when treatment is stopped. Norethisterone is partly metabolized to ethinylestradiol. Per one milligram of orally administered norethisterone, ethinylestradiol is formed equivalent to an oral dose of approximately 4 μg in humans. Since the estrogenicity of norethisterone has always been assumed and experienced in clinical practice, the recent discovery of its metabolic characteristics does not change the existing recommendations for use.
Elimination: Norethisterone is not excreted unchanged to a significant extent. Predominantly A-ring-reduced and hydroxylated metabolites as well as their conjugates (glucuronides and sulfates) are excreted via urine and feces. 37.4% to 80% of the orally administered dose was excreted in the urine over 5 days with a half-life of about 19 hours.
Steady-state conditions: During multiple-dose daily administration with norethisterone, an accumulation of the drug is unlikely because of the relatively short half-life of the drug. If, however, SHBG inducing agents such as ethinylestradiol are co-administered, an increase in norethisterone serum levels can occur because of the binding of norethisterone to SHBG.