Norethisterone, also known as norethindrone and sold under the brand name Norlutin among others, is a progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders.
of norethisterone include menstrual irregularities, , nausea, breast tenderness, mood changes, acne, hirsutism.
Norethisterone was discovered in 1951 and was one of the first progestins to be developed.
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 bone marrow transplantation, as it has been associated with substantially lower one-year survival post-transplantation.
Side effects
At contraceptive and hormone replacement dosages (0.35 to 1 mg/day), norethisterone has essentially progestogenic
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, norethisterone enanthate, 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. In clinical studies, the most common side effect with norethisterone enanthate has been menstrual disturbances, including prolonged bleeding or spotting and
amenorrhea.
Other side effects have included periodic abdominal bloating and breast tenderness, both of which are thought to be due to water retention and can be relieved with
.
There has been no association with
weight gain, and
blood pressure,
blood clotting, and glucose tolerance have all remained normal.
However, a decrease in
HDL cholesterol has been observed.
At high doses (5 to 60 mg/day), for instance those used in the treatment of gynecological disorders, norethisterone can cause hypogonadism due to its antigonadotropic effects and can have estrogenic and weak androgenic side effects.
High doses of norethisterone acetate (10 mg/day) have been associated with abnormal liver function tests, including significant elevations in liver enzymes.
Androgenic
Due to its weak androgenic activity, norethisterone can produce androgenic
such as
acne,
hirsutism, and
of slight severity in some women at high dosages (e.g., 10 to 40 mg/day).
This is notably not the case with combined oral contraceptives that contain norethisterone and EE, however.
Such formulations contain low dosages of norethisterone (0.35 to 1 mg/day)
in combination with estrogen and are actually associated with improvement in acne symptoms.
In accordance, they are in fact approved by the for the treatment of acne in women in the United States.
The improvement in acne symptoms is believed to be due to a 2- to 3-fold increase in sex hormone-binding globulin (SHBG) levels and a consequent decrease in free
testosterone levels caused by EE, which results in an overall decrease in androgenic signaling in the body.
The are highly androgen-sensitive and their size and activity are potential markers of androgenic effect.
A large clinical study of high to very high oral dosages of norethisterone (10 to 40 mg/day) administered for prolonged periods of time (4 to 35 weeks) to prevent miscarriage in pregnancy women found that 5.5% of the women experienced mild androgenic side effects such as mild (hoarseness), acne, and hirsutism and that 18.3% of female infants born to the mothers showed, in most cases only slight, virilization of the .
In a letter to the editor on the topic of virilization caused by high dosages of norethisterone acetate in women, a physician expressed that they had not observed the "slightest evidence of virilization" and that there had "certainly been no hirsutism nor any voice changes" in 55 women with advanced breast cancer that they had treated with 30 to 60 mg/day norethisterone for up to six months.
High-dosage norethisterone has been used to suppress menstruation in women with severe intellectual disability who were incapable of handling their own menses.
Estrogenic
Norethisterone is weakly estrogenic (via conversion into its
metabolite EE), and for this reason, it has been found at high dosages to be associated with high rates of estrogenic side effects such as breast enlargement in women and
gynecomastia in men, but also with improvement of
menopause in
fully menopausal women.
It has been suggested that very high dosages (e.g., 40 mg/day, which are sometimes used in clinical practice for various indications) of norethisterone acetate (and by extension norethisterone) may result in an increased risk of venous thromboembolism (VTE) analogously to high dosages (above 50 μg/day) of EE, and that even doses of norethisterone acetate of 10 to 20 mg, which correspond to EE doses of approximately 20 to 30 μg/day, may in certain women be associated with increased risk.
A study also found that ethinylestradiol and norethisterone had a greater influence on coagulation factors when the dose of norethisterone was 3 or 4 mg than when it was 1 mg.
This might have been due to additional ethinylestradiol generated by higher doses of norethisterone.
Overdose
There have been no reports of serious
with overdose of norethisterone, even in small children.
As such, overdose usually does not require treatment.
High dosages of as much as 60 mg/day norethisterone have been studied for extended treatment durations without serious adverse effects described.
Interactions
5α-Reductase plays an important role in the
metabolism of norethisterone, and 5α-reductase inhibitors such as
finasteride and
dutasteride can inhibit its metabolism. Norethisterone is partially metabolized via
hydroxylation by CYP3A4, and
enzyme inhibitor and
enzyme inducer of CYP3A4 can significantly alter circulating levels of norethisterone.
For instance, the CYP3A4 inducers
rifampicin and
bosentan have been found to decrease norethisterone exposure by 42% and 23%, respectively, and the CYP3A4 inducers
carbamazepine and St. John's wort have also been found to accelerate norethisterone clearance.
Pharmacology
Pharmacodynamics
Norethisterone is a potent progestogen and a weak
androgen and estrogen.
That is, it is a potent
agonist of the progesterone receptor (PR) and a weak agonist of the androgen receptor (AR) and the estrogen receptor (ER).
Norethisterone itself has insignificant affinity for the ER; its estrogenic activity is from an active metabolite that is formed in very small amounts,
ethinylestradiol (EE), which is a very potent estrogen.
Norethisterone and its metabolites have negligible affinity for the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) and hence have no
glucocorticoid, antiglucocorticoid, mineralocorticoid, or antimineralocorticoid activity.
Progestogenic activity
Norethisterone is a potent progestogen and binds to the PR with approximately 150% of the affinity of
progesterone.
In contrast, its parent compounds, testosterone,
nandrolone (19-nortestosterone), and
ethisterone (17α-ethynyltestosterone), have 2%, 22%, and 44% of the relative binding affinity of progesterone for the PR.
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
activity,
although its affinity for the PR is greatly reduced relative to norethisterone at only 25% of that of progesterone.
Norethisterone produces similar changes in the
endometrium and
vagina, such as
decidualization, and is similarly
antigonadotropic,
ovulation-inhibiting, and
thermogenesis in women compared to progesterone, which is in accordance with its progestogenic activity.
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.
In contrast to norethisterone, 5α-DHNET, the major metabolite of norethisterone, shows higher affinity for the AR, with approximately 27% of the affinity of metribolone.
However, although 5α-DHNET has higher affinity for the AR than norethisterone, it has significantly diminished and in fact almost abolished androgenic potency in comparison to norethisterone in rodent
.
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.
As such, it appears that the ethynyl group of norethisterone at the C17α position is responsible for its loss of androgenicity upon 5α-reduction.
Norethisterone (0.5 to 3 mg/day) has been found to dose-dependently decrease circulating SHBG levels, which is a common property of androgens and is due to AR-mediated suppression of hepatic SHBG production.
Norethisterone is bound to a considerable extent (36%) to SHBG in circulation.
Estrogenic activity
Norethisterone binds to the ERs, the ERα and the ERβ, with 0.07% and 0.01% of the relative binding affinity of estradiol.
Due to these very low relative affinities, it is essentially inactive itself as a ligand of the ERs at clinical concentrations.
However, norethisterone has been found to be a substrate for
aromatase and is converted in the
liver to a small extent (0.35%) to the highly potent estrogen
ethinylestradiol (EE), and for this reason, unlike most other progestins, norethisterone has some estrogenic activity.
However, with typical dosages of norethisterone used in oral contraceptives (0.5 to 1 mg), the levels of EE produced are low, and it has been said that they are probably without clinical relevance.
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
.
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
enzyme 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).
Other activities
Norethisterone is a very weak inhibitor of CYP2C9 and CYP3A4 (IC
50 = 46 μM and 51 μM, respectively), but these actions require very high concentrations of norethisterone that are far above therapeutic circulating levels (which are in the nanomolar range) and hence are probably not clinically relevant.
Norethisterone and some of its 5α-reduced metabolites have been found to produce vasodilator effects in animals that are independent of sex steroid receptors and hence appear to be non-genomic in mechanism.
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).
Antigonadotropic effects
Due to its progestogenic activity, norethisterone suppresses the hypothalamic–pituitary–gonadal axis (HPG axis) and hence has
antigonadotropic effects.
The estrogenic activity of norethisterone at high doses would also be expected to contribute to its antigonadotropic effects.
Due to its antigonadotropic effects, norethisterone suppresses
sex hormone biosynthesis, 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.
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 single 200 mg intramuscular injection of norethisterone enanthate alone or in combination with 2 mg estradiol valerate has been found to produce a rapid, strong, and sustained decrease in gonadotropin and testosterone levels for up to one month in men.
Pharmacokinetics
The
pharmacokinetics of norethisterone have been reviewed.
Absorption
The oral
bioavailability of norethisterone is between 47 and 73%, with a mean oral bioavailability of 64%.
has been found to significantly improve the oral bioavailability of norethisterone by increasing
intestinal absorption and reducing
intestinal metabolism.
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.
Distribution
The plasma protein binding of norethisterone is 97%.
It is bound 61% bound to albumin and 36% bound to SHBG.
Metabolism
Norethisterone has an elimination half-life of 5.2 to 12.8 hours, with a mean elimination half-life of 8.0 hours.
The
metabolism of norethisterone is very similar to that of testosterone (and nandrolone) and is mainly via reduction of the Δ
4 double bond to 5α- and 5β-dihydronorethisterone, which is followed by the reduction of the C3
ketone functional group to the four
of 3,5-tetrahydronorethisterone.
These transformations are catalyzed by 5α- and 5β-reductase and 3α- and 3β-hydroxysteroid dehydrogenase both in the
liver and in extrahepatic tissues such as the
pituitary gland,
uterus,
prostate gland,
vagina, and
breast.
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.
Norethisterone is metabolized in the liver via
hydroxylation as well, mainly by CYP3A4.
Some conjugation (including
glucuronidation and
sulfation)
of norethisterone and its metabolites occurs in spite of
steric hindrance by the
ethynyl group at C17α.
The ethynyl group of norethisterone is preserved in approximately 90% of all of its metabolites.
Norethisterone is used in birth control pills, opposed to progesterone itself, because it is not metabolized as rapidly as progesterone when consumed orally. When progesterone is consumed orally it is rapidly metabolized in the gastrointestinal tract and the liver, and broken down into many different metabolites. Whereas, norethisterone is not as rapidly metabolized allowing norethisterone to be present in higher quantities allowing it to more effectively compete for progesterone receptor binding sites.
Elimination
Norethisterone is eliminated 33 to 81% in
urine and 35 to 43% in
feces.
Chemistry
Norethisterone, also known as 17α-ethynyl-19-nortestosterone or as 17α-ethynylestra-4-en-17β-ol-3-one, is a synthetic
estrane steroid and a derivative of
testosterone.
It is specifically a derivative of testosterone in which an
ethynyl group has been added at the C17α position and the
methyl group at the C19 position has been removed; hence, it is a combined derivative of
ethisterone (17α-ethynyltestosterone) and
nandrolone (19-nortestosterone).
These modifications result in increased progestogenic activity and oral
bioavailability as well as decreased
androgenic/
anabolic activity.
Derivatives
Norethisterone (NET) is the
parent compound of a large group of progestins that includes most of the progestins known as the 19-nortestosterone derivatives.
This group is divided by chemical structure into the
(derivatives of norethisterone) and the
(18-methylgonanes or 13β-ethylestranes; derivatives of
levonorgestrel) and includes the following marketed medications:
- Estranes
-
Etynodiol diacetate (3β-hydroxy-NET 3β,17β-diacetate)
-
Lynestrenol (3-desoxy-NET)
-
Norethisterone acetate (NET 17β-acetate)
-
Norethisterone enanthate (17β-enanthate)
-
Noretynodrel (δ5(10)-NET)
-
Norgestrienone (δ9,11-NET)
-
Quingestanol acetate (NET 17β-acetate 3-cyclopentyl enol ether)
-
Tibolone (7α-methyl-δ5(10)-NET)
- Gonanes
Several of these act as of norethisterone, including norethisterone acetate, norethisterone enanthate, etynodiol diacetate, lynestrenol, and quingestanol acetate.
Non-17α-ethynylated
19-Nortestosterone (19-NT) progestins which are technically not derivatives of norethisterone (as they do not have a C17α
ethynyl group) but are still closely related (with other substitutions at the C17α and/or C16β positions) include the following marketed medications:
Many of the 19-nortestosterone family, like norethandrolone and ethylestrenol, are also potent progestogens, but were never marketed as such.
Synthesis
Chemical syntheses of norethisterone have been published.
Synthesis 1
Estradiol 3-methyl ether (
1, EME) is partially reduced to the 1,5-diene (
2) as also occurs for the first step in the synthesis of nandrolone. Oppenauer oxidation then transforms the C17β hydroxyl group into a ketone functionality (
3). This is then reacted with metal
acetylide into the corresponding C17α
ethynyl compound (
4). Hydrolysis of the enol ether under mild conditions leads directly to (
5),
[ which appears to be noretynodrel (although Lednicer states that it is "etynodrel" in his book (which may be a synonym etynodiol); etynodrel is with a chlorine atom attached), an orally active progestin. This is the progestogen component of the first oral contraceptive to be offered for sale (i.e., Enovid). Treatment of the ethynyl enol ether with strong acid leads to norethisterone ( 6).]
In practice, these and all other combined oral contraceptives are mixtures of 1 to 2% EE or mestranol and an oral progestin. It has been speculated that the discovery of the necessity of estrogen in addition to progestin for contraceptive efficacy is due to the presence of a small amount of unreduced EME ( 1) in early batches of 2. This when subjected to oxidation and alkynylation, would of course lead to mestranol ( 3). In any event, the need for the presence of estrogen in the mixture is now well established experimentally.
Synthesis 2
Norethisterone is made from estr-4-ene-3,17-dione (bolandione), which in turn is synthesized by partial reduction of the aromatic region of the 3-O-methyl ether of estrone with lithium in liquid ammonia, and simultaneously of the keto group at C17α to a hydroxyl group, which is then oxidized back to a keto group by chromium trioxide in acetic acid. The conjugated C4-C5 olefin and the carbonyl group at C3 is then transformed to dienol ethyl ether using ethyl orthoformate. The obtained product is ethynylated by acetylene in the presence of potassium tert-butoxide. After hydrochloride hydrolysis of the formed O-potassium derivative, during which the enol ether is also hydrolyzed, and the remaining double bond is shifted, the desired norethisterone is obtained.
History
Norethisterone was synthesized for the first time by chemists Luis Miramontes, Carl Djerassi, and George Rosenkranz at Syntex in Mexico City in 1951.
Society and culture
Generic names
Norethisterone is the and of the drug while norethindrone is its .
Brand names
Norethisterone is available in Bangladesh as Menogia (ACI), Normens (Renata) etc. Norethisterone (NET), including as norethisterone acetate and norethisterone enanthate, has been marketed under many brand names throughout the world.
Availability
United States
Norethisterone was previously available alone in 5 mg tablets under the brand name Norlutin in the United States, but this formulation has since been discontinued.
Both norethisterone and norethisterone acetate are also available in the United States as contraceptives.
Research
Norethisterone, as norethisterone acetate and norethisterone enanthate, has been studied for use as a potential male hormonal contraceptive in combination with testosterone in men.
Long-acting norethisterone for intramuscular injection have been studied for potential use in birth control.
Further reading
