Norethisterone

Norethisterone is a synthetic progestin, a type of hormone similar to the progesterone naturally produced by the ovaries. It is used for various medical purposes, primarily in gynecology. Norethisterone is combined with estrogen in some forms of oral contraceptives (birth control pills). It helps prevent pregnancy by inhibiting ovulation (release of an egg from the ovary), thickening cervical mucus to prevent sperm from reaching the egg, and altering the lining of the uterus.

Norethisterone is also prescribed to treat menstrual disorders. It may regulate irregular menstrual cycles, address heavy menstrual bleeding (menorrhagia), and manage premenstrual syndrome (PMS) symptoms.

Norethisterone is sometimes used to manage endometriosis, a condition where tissue similar to the lining of the uterus grows outside the uterus. It helps reduce symptoms associated with endometriosis, such as pain and abnormal bleeding.

 In some hormone replacement therapy regimens for postmenopausal women, norethisterone is combined with estrogen to protect against the development of endometrial hyperplasia (abnormal thickening of the lining of the uterus).

Norethisterone can be used to delay the onset of menstruation for specific reasons, such as travel plans or special events. It is typically taken in the days leading up to the expected period.

Norethisterone is available in various forms, including oral tablets and injections.

Common side effects of norethisterone may include nausea, headache, breast tenderness, and changes in menstrual bleeding. Serious side effects are rare but can include blood clots, especially in individuals who smoke or have other risk factors.

Norethisterone may not be suitable for individuals with certain medical conditions, such as a history of blood clots, liver disease, or certain cancers. It’s essential to inform the healthcare provider of any existing health conditions.

Norethisterone is not intended for use during pregnancy, and its safety during breastfeeding is not well established. It’s essential to consult with a healthcare provider if pregnancy is suspected.

As with any medication, norethisterone should be used under the guidance of a healthcare professional who can assess its appropriateness for individual needs and monitor for potential side effects.

Pharmacokinetics

Norethisterone is absorbed from the gastrointestinal tract, undergoing first-pass hepatic metabolism, with peak plasma concentrations occurring 1 to 2 hours after an oral dose. It exhibits biphasic pharmacokinetics. An initial distribution phase is followed by a prolonged elimination phase with a half-life of about 8 hours or more. Norethisterone is highly protein-bound, about 60% to albumin and 35% to sex hormone-binding globulin. The use of the medicine with estrogen increases the proportion bound to sex hormone-binding globulin. It is metabolized in the liver, with 50 to 80% of a dose excreted in the urine and up to 40% appearing in the feces.

Norethisterone acetate is rapidly hydrolyzed to norethisterone, principally by intestinal tissue. After intramuscular injection of norethisterone enantate, peak concentrations of norethisterone in plasma are not attained for several days.

Uses and Administration

Norethisterone and its acetate and enanthate esters are progestogens derived from nortestosterone with weak oestrogenic and androgenic properties. They are commonly used as hormonal contraceptives. Norethisterone and norethisterone acetate are both given orally. Typical daily doses are 350 micrograms for norethisterone and 600 micrograms for norethisterone acetate when used alone, or 0.5 to 1 mg for norethisterone and 1 to 1.5 mg for norethisterone acetate when used with an estrogen. Norethisterone enantate is given by intramuscular injection; a dose of 200 mg provides contraception for eight weeks. An intramuscular injection containing norethisterone enantate 50 mg with estradiol valerate 5 mg is given once each month.

Norethisterone and norethisterone acetate are used as the progestogen component of menopausal HRT. Typical regimens have included either continuous daily doses of norethisterone 700 micrograms or norethisterone acetate 0.5 to 1 mg or cyclical regimens of norethisterone or norethisterone acetate 1 mg daily for 10 to 12 days of a 28-day cycle. Norethisterone acetate is also available as transdermal patches supplying 140, 170, or 250 micrograms in 24 hours that are applied twice weekly for two weeks of a 4-week cycle; the lower strengths may also be applied twice weekly continuously.

Norethisterone and norethisterone acetate may be given orally, usually in divided doses, to treat conditions such as menorrhagia (below) and endometriosis. In menorrhagia (dysfunctional uterine bleeding), norethisterone is given in usual doses of 10 to 15 mg daily and norethisterone acetate in doses of 2.5 to 10 mg daily in a cyclical regimen. In endometriosis, the dosage of norethisterone is 10 to 25 mg daily, and norethisterone acetate is 5 to 15 mg daily. Treatment of endometriosis is usually continuous for 4 to 9 months.

Norethisterone has been used in daily doses of up to 15 mg orally in a cyclical regimen to treat premenstrual syndrome. Oral doses of up to 60 mg daily of norethisterone have been used in breast cancer.

Administration in Children

Although unlicensed in the UK for use in children, the BNFC does include norethisterone for managing delayed puberty in girls. After 12 to 24 months of estrogen therapy, it is added to establish a menstrual cycle and maintain sexual maturation in an oral dose of 5 mg once daily for the last seven days of a 28-day cycle.

Menorrhagia

Although cyclical norethisterone has been widely used for menorrhagia, it is of limited efficacy during ovulatory cycles, being most effective for anovulatory bleeding, which occurs in a minority of women with menorrhagia.

Adverse Effects and Precautions

Norethisterone, like any medication, may cause adverse effects in some individuals. It’s essential to be aware of potential side effects and take necessary precautions when using this medication. 

Adverse Effects

1. Common Side Effects: Common side effects of norethisterone may include nausea, headache, breast tenderness, and changes in menstrual bleeding. These side effects are usually mild and temporary.
2. Irregular Bleeding: Norethisterone can cause changes in menstrual bleeding patterns, including breakthrough bleeding or spotting between periods. This is more common during the first few months of use.
3. Mood Changes: Some individuals may experience mood changes, including irritability or mood swings.
4. Fluid Retention: Fluid retention and bloating may occur as a side effect of norethisterone.
5. Headache and Migraine: Headaches and migraines have been reported in some individuals using norethisterone.
6. Breast Discomfort: Breast tenderness or discomfort may occur.
7. Blood Clots: While the risk is generally low, hormonal contraceptives, including norethisterone-containing products, have been associated with an increased risk of blood clots, particularly in individuals who smoke or have other risk factors.
8. Allergic Reactions: Allergic reactions to norethisterone are rare but can occur. Seek medical attention if you experience symptoms of an allergic reaction, such as rash, itching, swelling, severe dizziness, or difficulty breathing.

Precautions

1. Smoking and Age: The risk of blood clots is increased in individuals who smoke, especially those over 35. It’s advisable to avoid smoking while using norethisterone.
2. History of Blood Clots: Individuals with a history of blood clots or certain cardiovascular conditions may need to avoid or use norethisterone cautiously. Discuss your medical history with your healthcare provider.
3. Liver Disorders: Norethisterone is metabolized in the liver, and individuals with liver disorders may require monitoring or dosage adjustments.
4. Cancer Risk: There may be an increased risk of certain cancers, including breast cancer, associated with hormonal contraceptives. Regular breast examinations are recommended.
5. Pregnancy and Breastfeeding: Norethisterone is not intended for use during pregnancy. If pregnancy is suspected, consult with a healthcare provider. While small amounts of the hormone may pass into breast milk, the safety during breastfeeding is generally considered acceptable.
6. Interactions with Other Medications: Norethisterone can interact with certain medications, including some anticonvulsants, antibiotics, and antiretroviral drugs. Inform your healthcare provider about all medications you are taking.

Always use norethisterone under the guidance of a healthcare professional. Contact your healthcare provider for advice if you experience severe or persistent side effects. Individual responses to medications can vary, and your healthcare provider can help determine the most suitable contraceptive or hormonal therapy for your specific needs.

Effects on the Liver

There were 6 cases of jaundice among 107 patients with breast cancer treated with high-dose norethisterone acetate. The jaundice was reversible and of an obstructive type. A retrospective analysis found that using norethisterone to prevent menstrual bleeding during the thrombocytopenic phase of allogeneic bone marrow transplantation was a significant risk factor for hepatic veno-occlusive disease.

Porphyria

Norethisterone is associated with acute porphyria attacks and is considered unsafe in patients with porphyric.

Pregnancy

Abnormalities seen in the children of women given norethisterone during pregnancy (either alone or with ethinylestradiol) included hypospadias, masculinization of female infants, meningomyelocele or hydrocephalus, and neonatal choreoathetosis associated with oral contraceptive use.

Venous Thromboembolism

Combined oral contraceptives containing older progestogens such as norethisterone appear to be associated with a lower incidence of venous thromboembolism than desogestrel- or gestodene-containing preparations.

Interactions

Like many medications, Norethisterone can interact with other drugs, potentially affecting their effectiveness or increasing the risk of side effects. You must inform your healthcare provider about all medications, supplements, and over-the-counter drugs you are taking. Here are some potential interactions with norethisterone:

1. Antibiotics: Some antibiotics, such as rifampin, rifabutin, and certain tetracyclines, may decrease the effectiveness of norethisterone. Additional contraceptive measures may be needed if antibiotics are used concurrently.
2. Anticonvulsants: Certain anticonvulsant medications, including phenytoin, carbamazepine, and barbiturates, may reduce the effectiveness of hormonal contraceptives like norethisterone. Concomitant use may necessitate additional contraceptive methods.
3. Antiretroviral Drugs: Some antiretroviral medications used in treating HIV, such as ritonavir, can interact with norethisterone, potentially affecting its levels in the blood.
4. St. John’s Wort: St. John’s Wort, a herbal supplement, is known to induce the metabolism of certain drugs, including hormonal contraceptives. Its use with norethisterone may reduce its effectiveness.
5. Ciclosporin: Ciclosporin, an immunosuppressive medication, may increase the levels of norethisterone in the blood, leading to an increased risk of side effects.
6. Warfarin: Norethisterone may interact with warfarin, an anticoagulant, potentially affecting blood clotting parameters. Monitoring is advisable if these medications are used together.
7. Selective Serotonin Reuptake Inhibitors (SSRIs): Certain SSRIs, such as fluoxetine and paroxetine, may interact with norethisterone, affecting its metabolism.
8. CYP3A4 Inhibitors: Medications that inhibit the enzyme CYP3A4, such as ketoconazole and itraconazole (antifungals), can potentially increase norethisterone levels in the blood.
9. Herbal Supplements: Other herbal supplements, besides St. John’s Wort, may interact with norethisterone. You must inform your healthcare provider about all supplements you are taking.
10. Grapefruit Juice: Grapefruit juice can inhibit the metabolism of certain drugs, potentially leading to increased levels in the blood. While the evidence for an interaction with norethisterone is limited, it’s advisable to exercise caution.

This list is not exhaustive, and individual responses to medications can vary. Always provide a comprehensive list of your medications and supplements to your healthcare provider to ensure norethisterone’s safe and effective use. They can help assess potential interactions and adjust your treatment plan accordingly.

Drug Nomenclature

Synonyms: Ethinylnortestosterone; NSC-9564; Norethindrone; Norethisteron; Norethisteronum; Noretisteron; Noretisterona; Noretisteronas; Noretisterone; Noretisteroni; Noretiszteron; Norpregneninolone

BAN: Norethisterone

INN: Norethisterone [pINN (en)]

INN: Noretisterona [pINN (es)]

INN: Noréthistérone [pINN (fr)]

INN: Norethisteronum [pINN (la)]

INN: Норэтистерон [pINN (ru)]

Chemical name: 17β-Hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one

Molecular formula: C20H26O2 =298.4

CAS: 68-22-4

ATC code: G03AC01; G03DC02

Read code: y00VA [Progestogen Oral Contraceptive]; y00XI [Malignancy]; y02bO; y07kF; y00V7 [Combined Oral Contraceptive]; y08DZ [Endocrine]

Pharmacopoeias. In China, Europe, International, Japan, and the US.

European Pharmacopoeia, 6th ed. (Norethisterone). A white or yellowish-white crystalline powder. It is practically insoluble in water, sparingly soluble in dehydrated alcohol, and in acetone, soluble in dichloromethane.

The United States Pharmacopeia 31, 2008 (Norethindrone). A white to creamy-white odorless crystalline powder. It is practically insoluble in water, sparingly soluble in alcohol, soluble in chloroform and dioxane, and slightly soluble in ether.

Norethisterone Acetate

Drug Nomenclature

Synonyms: Norethindrone Acetate; Norethisteron-acetát; Norethisteroni Acetas; Noretisterona, acetato de; Noretisteronacetat; Noretisteroniasetaatti; Noretisterono acetatas; Noretiszteron-acetát

BAN: Norethisterone Acetate [BANM]

INN: Norethisterone Acetate [pINNM (en)]

INN: Acetato de noretisterona [pINNM (es)]

INN: Noréthistérone, Acétate de [pINNM (fr)]

INN: Norethisteroni Acetas [pINNM (la)]

INN: Норэтистерона Ацетат [pINNM (ru)]

Chemical name: 17β-Hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one acetate; 3-Oxo-19-nor-17α-pregn-4-en-20-yn-17β-yl acetate

Molecular formula: C22H28O3 =340.5

CAS: 51-98-9

ATC code: G03AC01; G03DC02

Pharmacopoeias. In Europe, International, and in the US.

European Pharmacopoeia, 6th ed. (Norethisterone Acetate). A white or yellowish-white crystalline powder. It exhibits polymorphism. Practically insoluble in water, soluble in alcohol, and freely soluble in dichloromethane. Protect from light.

The United States Pharmacopeia 31, 2008 (Noneth in drone Acetate). A white to creamy-white odorless crystalline powder. Practically insoluble in water, soluble 1 in 10 of alcohol, 1 in less than 1 of chloroform, 1 in 2 of dioxane, and 1 in 18 of ether.

Norethisterone Enantate

Drug Nomenclature

Synonyms: Norethindrone Enanthate; Norethisterone Enanthate; Norethisterone Heptanoate; Noretisterona, enantato de

BAN: Norethisterone Enantate [BANM]

INN: Norethisterone Enantate [pINNM (en)]

INN: Enantato de noretisterona [pINNM (es)]

INN: Noréthistérone, Enantate de [pINNM (fr)]

INN: Norethisteroni Enantas [pINNM (la)]

INN: Норэтистерона Енантат [pINNM (ru)]

Chemical name: 17β-Hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one heptanoate

Molecular formula: C27H38O3 =410.6

CAS: 3836-23-5

ATC code: G03AC01; G03DC02

Read code: y00VB

Pharmacopoeias. In International