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Norethisterone

 

Norethisterone, also known as norethindrone.

 

 

 A progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders.

 

 

The medication available in both low-dose and high-dose formulations and both alone and in combination with an estrogen.

 

 

Can be used by mouth or, as norethisterone enanthate, by injection into muscle.

 

 

Trade names; numerous.

 

 

Bioavailability 47–73% (mean 64%.

 

 

Protein binding 97%.

 

 

Albumin: 61%

 

 

SHBG: 36%

 

 

Metabolism: Mainly CYP3A4 (liver.

 

 

Elimination half-life 5.2–12.8 hours (mean 8.0 hours)

 

 

Side effects include: menstrual irregularities, headaches, nausea, breast tenderness, mood changes, acne, increased hair growth.

 

 

It is a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progesterone.

 

 

It has weak androgenic and estrogenic activity, mostly at high dosages.

 

 

It is used as a hormonal contraceptive in combination with an estrogen – usually ethinylestradiol, in combined oral contraceptive pills and alone in progestogen-only pills.

 

 

It is  used of norethisterone is to alleviate endometriosis related pain, by inducing endometrial proliferation during secretory phase.

 

 

It inhibition of ovulation and reduces pain and discomfort is that is made worse worse during ovulation.

 

 

Contraindications to use: 

 

 

High-dose (10 mg/day) norethisterone has been associated with hepatic veno-occlusive disease, and should not be given to patients undergoing allogeneic bone marrow transplantation.

 

 

At contraceptive and hormone replacement dosages (0.35 to 1 mg/day), it has essentially progestogenic side effects only. 

 

 

In most clinical studies for contraception or menopausal hormone therapy, the drug has been combined with an estrogen, and it is difficult to determine which of the side effects were caused by norethisterone and which of them were caused by estrogen.

 

 

Most common side effects: menstrual disturbances, including prolonged bleeding or spotting and amenorrhea, periodic abdominal bloating and breast tenderness, both due to water retention.

 

 

Therehas been no association with weight gain, and blood pressure, blood clotting, and glucose intolerance.

 

 

A decreased in HDL cholesterol has been observed.

 

 

At doses (5 to 60 mg/day) used in the treatment of gynecological disorders, it can cause hypogonadism due to its antigonadotropic effects and can have estrogenic and weak androgenic side effects.

 

 

High doses have been associated with abnormal liver function tests: lactate dehydrogenase and glutamate pyruvate transaminase.

 

 

It has weak androgenic activity,  but can produce androgenic side effects such as acne, hirsutism, and voice changes of slight severity in some women at high dosages.

 

 

It is approved for the treatment of acne in women in the United States due to a 2- to 3-fold increase in sex hormone-binding globulin (SHBG) levels.

 

 

The sebaceous glands are highly androgen-sensitive and their size and activity are potential markers of androgenic effect.

 

 

A high dosage of 20 mg/day norethisterone has been found to significantly stimulate the sebaceous glands, whereas lower dosages of 5 mg/day and 2.5 mg/day do not significantly stimulate sebum production and are regarded as devoid of significant androgenicity.

 

 

Conversely, dosages of norethisterone of 0.5 to 3 mg/day have been found to decrease SHBG levels by suppress hepatic SHBG production, which is another highly sensitive marker of androgenicity.

 

 

The use 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 pregnant women found that 5.5% of the women experienced androgenic side effects:  hoarseness, acne, and hirsutism and that 18% of female infants born to the mothers showed slight, virilization of the genitals.

 

 

A study of 118 nulliparous women treated with 5 mg/day norethisterone for a period of 2 to 30 months found that the drug was effective in producing amenorrhea in 86% of the women, with breakthrough bleeding occurring in the remaining 14%.

 

 

Little to no risk of androgenic side effects with norethisterone at a dosage of 5 mg/day.

 

 

A study of 194 women treated with 5 to 15 mg/day NETA for a median duration of 13 months: observed no side effects in 55.2% of patients, weight gain in 16.1%, acne in 9.9%, mood lability in 8.9%, hot flashes in 8.3%, and voice deepening in 1.0%.

 

 

It is weakly estrogenic, and at high dosages is associated with high rates of estrogenic side effects such as breast enlargement in women and gynecomastia in men, and  with improvement of menopausal symptoms in postmenopausal women.

 

 

5α-reductase inhibitors such as finasteride and dutasteride can inhibit its metabolism.

 

 

It is partially metabolized via hydroxylation by CYP3A4, and inhibitors and inducers of CYP3A4 can significantly alter circulating levels of norethisterone.

 

 

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.

 

 

It is a potent progestogen and a weak androgen and estrogen.

 

 

A potent agonist of the progesterone receptor (PR) and a weak agonist of the androgen receptor (AR) and the estrogen receptor (ER).

 

 

Norethisterone is a potent progestogen and binds to the PR with approximately 150% of the affinity of progesterone.

 

 

Norethisterone produces endometrial transformation, and is similarly antigonadotropic, ovulation-inhibiting, and thermogenic in women compared to progesterone.

 

 

Norethisterone dose-dependently decreases circulating SHBG levels, is due to androgen mediated suppression of hepatic SHBG production.

 

 

It also 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 is bound 36% to SHBG in circulation.

 

 

It has lower affinity for SHBG than endogenous androgens and estrogens,

 

 

It may displace testosterone from SHBG and thereby increase free testosterone levels, and this action may contribute to its weak androgenic effects.

 

 

Ethinylestradiol is the metabolite of norethisterone responsible for its 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, and is essentially inactive itself as a ligand of the ERs at clinical concentrations.

 

 

Norethisterone is a substrate for aromatase and is converted in the liver to a small extent (0.35%) to the highly potent estrogen EE.

 

 

Therefore, norethisterone has some estrogenic activity, but with typical dosages of norethisterone used in oral contraceptives (0.5 to 1 mg), the levels of EE produced are low, and probably without clinical relevance.

 

 

At high doses, it may increase the risk of venous thromboembolism due to metabolism into EE.

 

 

Like progesterone and testosterone, norethisterone is metabolized into 3,5-tetrahydro metabolites.

 

 

It is a substrate for and is known to be an inhibitor of 5alpha reductase: but this action may not be clinically relevant at typical dosages.

 

 

Norethisterone and its major active metabolite have been found to act as irreversible aromatase inhibitors, but 

 

the concentrations required are probably too high to be clinically relevant at typical dosages.

 

 

Norethisterone is a very weak inhibitor of CYP2C9 and CYP3A4, and hence are probably not clinically relevant.

 

 

Norethisterone suppresses the hypothalamic–pituitary–gonadal axis (HPG axis) and hence has antigonadotropic effects.

 

 

The estrogenic activity of norethisterone at high doses contributes to its antigonadotropic effects.

 

 

Due to its antigonadotropic effects, norethisterone suppresses gonadal sex hormone production, inhibits ovulation in women, and suppresses spermatogenesis in men.

 

 

A single 200 mg intramuscular injection produces a rapid, strong, and sustained decrease in gonadotropin and testosterone levels for up to one month in men.

 

 

Intramuscular injections of 200 mg once every 3 weeks have also been found to suppress spermatogenesis in men.

 

 

The oral bioavailability of norethisterone is at a mean of 64%.

 

 

Micronization improves the oral bioavailability  by increasing intestinal absorption and reducing intestinal metabolism.

 

 

The plasma protein binding of norethisterone is 97%.

 

 

It is bound 61% bound to albumin and 36% bound to SHBG.

 

 

Metabolism of norethisterone: Norethisterone acetate, norethisterone enanthate, etynodiol, etynodiol diacetate, lynestrenol, noretynodrel, quingestanol, and quingestanol acetate are all prodrugs of norethisterone.

 

 

Ethinylestradiol is an estrogenic metabolite of norethisterone formed by cytochrome P450 enzymes. 

 

 

Norethisterone and its metabolites also undergo hydroxylation via cytochrome P450 enzymes and conjugation via glucuronidation and sulfation at available hydroxyl (–OH) groups, and has an elimination half-life of 5.2 to 12.8 hours.

 

 

The metabolism of norethisterone is very similar to that of testosterone.

 

 

It is used in birth control pills, opposed to progesterone itself, because it is not metabolized as rapidly as progesterone when consumed orally: progesterone consumed orally it is rapidly metabolized in the gastrointestinal tract and the liver, and broken down into many different metabolites. 

 

 

Norethisterone is not as rapidly metabolized allowing it to be present in higher quantities and to more effectively compete for progesterone receptor binding sites. 

 

 

It is eliminated 33 to 81% in urine and 35 to 43% in feces.

 

 

It is a synthetic estrane steroid and a derivative of testosterone.

 

 

It is a combined derivative of ethisterone and nandrolone.

 

 

It has increased progestogenic activity,  oral bioavailability as well as decreased androgenic/anabolic activity.

 

 

It is compound of a large group of progestins that includes most of the progestins known as the 19-nortestosterone derivatives.

 

 

Norethisterone was subsequently introduced in combination with mestranol as Ortho-Novum in the United States in 1963.

 

 

It is one of the only non-contraceptive progestogen-only drug formulations that remains available in the United States: others include progesterone, medroxyprogesterone acetate, megestrol acetate, and hydroxyprogesterone caproate, as well as the atypical agent danazol.

 

 

It is available as a contraceptive.

 

 

 

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