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Norethisterone | CAS No: 68-22-4 | GMP-certified suppliers
A medication that provides hormonal contraception, manages postmenopausal osteoporosis and vasomotor symptoms, and treats endometriosis-related pain when combined with specific agents.
Therapeutic categories
Primary indications
- Norethisterone is indicated as an oral contraceptive when given as monotherapy or in combination with an estrogen component, such as [ethinylestradiol] or [estradiol]
- In combination with an estrogen component, oral norethisterone is also indicated as a hormone replacement therapy in the treatment of postmenopausal osteoporosis and moderate-to-severe vasomotor symptoms arising from menopause
- When applied via transdermal patch, the combination of norethisterone and estradiol is indicated for the treatment of hypoestrogenism, vulvovaginal atrophy, and moderate-severe vasomotor symptoms
Product Snapshot
- Norethisterone is available mainly as an oral small molecule in various tablet formulations, with additional options including transdermal patches and intramuscular injections
- It is primarily used for oral contraception, hormone replacement therapy to manage menopausal symptoms and osteoporosis, and, in combination with leuprolide, for treatment of endometriosis-related pain
- Norethisterone holds regulatory approvals in key markets including the US, Canada, and the EU
Clinical Overview
Pharmacodynamically, norethisterone mimics endogenous progesterone with greater potency. Its contraceptive effect arises from multiple actions at the pelvic level: altering cervical mucus to increase viscosity and reduce sperm migration, inducing endometrial changes that impede implantation, and suppressing hypothalamic-pituitary gonadotropin release to prevent follicular maturation, ovulation, and corpus luteum formation. In hormone replacement therapy, norethisterone mitigates estrogen-induced endometrial proliferation, thereby reducing the associated risk of endometrial hyperplasia and carcinoma.
At the molecular level, norethisterone binds progesterone receptors distributed in reproductive tissues, central nervous system, breast, pituitary, and skeletal system, modulating gene expression. While its affinity for non-progesterone steroid receptors such as androgen and glucocorticoid receptors is low, some androgenic side effects like acne and lipid profile alterations have been observed, likely due to minimal androgen receptor activation.
Key ADME characteristics include oral bioavailability and metabolism predominantly via cytochrome P450 enzymes, including CYP3A4, CYP2C19, CYP1A2, and CYP2A6, with known substrate and inducer properties that may impact drug-drug interactions. Careful consideration should be given to potential alterations in hepatic metabolism when co-administered with CYP modulators.
Safety considerations include a reported slight increase in breast cancer risk with combined hormonal contraceptives, necessitating patient counseling and routine breast examinations. Other adverse effects stem from hormonal modulation and androgenic activity.
Notable formulations include oral contraceptive pills and transdermal patches with combined estrogen components. The API is widely approved globally and constitutes an integral component in contraceptive and hormone replacement regimens.
For API procurement, emphasis should be placed on stringent quality control measures to ensure purity, consistent potency, and compliance with pharmacopoeial standards. Given its metabolism via cytochrome P450 enzymes, impurities or batch variability could influence therapeutic performance and safety. Suppliers should provide comprehensive certificates of analysis and support regulatory filings to facilitate global market access.
Identification & chemistry
| Generic name | Norethisterone |
|---|---|
| Molecule type | Small molecule |
| CAS | 68-22-4 |
| UNII | T18F433X4S |
| DrugBank ID | DB00717 |
Pharmacology
| Summary | Norethisterone is a synthetic progestin that primarily targets progesterone receptors to modulate gene expression in reproductive tissues, the central nervous system, and related organs. Its pharmacological effects include altering cervical mucus to inhibit sperm migration, inducing endometrial changes to prevent implantation, and suppressing hypothalamic-pituitary hormones to inhibit ovulation and follicular development. Additionally, norethisterone has minimal activity at androgen and glucocorticoid receptors, which may contribute to certain side effects. |
|---|---|
| Mechanism of action | On a molecular level, progestins like norethisterone exert their effects on target cells via binding to progesterone receptors that result in downstream changes to target genes. Target cells are found in the reproductive tract, breast, pituitary, hypothalamus, skeletal tissue, and central nervous system. Contraceptive efficacy is derived mainly from changes to the cervical mucus, wherein norethisterone increases the cell content and viscosity of the mucous to impede sperm transport and migration. Norethisterone also induces a variety of changes to the endometrium - including atrophy, irregular secretion, and suppressed proliferation - that make it inhospitable for implantation. Working via a negative feedback loop, norethisterone also acts on both the hypothalamus and anterior pituitary to suppress the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. Suppression of these hormones prevents follicular development, ovulation, and corpus luteum development. When used as a component of hormone replacement therapy in menopausal women, norethisterone’s value is mainly in suppressing the growth of the endometrium. As estrogen stimulates endometrial growth, the unopposed use of estrogen in postmenopausal women with an intact uterus can lead to endometrial hyperplasia which can increase the risk of endometrial cancer. The addition of a progestin to a hormone replacement therapy in this population protects against this endometrial hyperplasia and, therefore, lowers the risk associated with the use of hormone replacement therapies. Norethisterone, along with other progestins and endogenous progesterone, has a low affinity for other steroid receptors, such as the androgen receptor and glucocorticoid receptor. While affinity and agonistic activity at these receptors is minimal, it is thought that androgen receptor agonism is responsible for some of the adverse effects observed with progestin use (e.g. acne, serum lipid changes). |
| Pharmacodynamics | Norethisterone is a synthetic oral progestin used for contraception or to treat other hormone-related conditions such as menopausal symptoms and endometriosis. As a synthetic progestin, norethisterone acts similarly to endogenous progesterone but with a much higher potency - it acts at the pelvic level to alter cervical and endometrial function, as well as via the inhibition of pituitary hormones that play a role in follicular maturation and ovulation. A small increase in the risk of developing breast cancer has been observed in patients using combined oral contraceptives, with some evidence also implicating progestin-only pills - patients starting hormonal contraception should be advised of this risk and should employ routine breast self-examinations to check for evidence of any developing masses. |
Targets
| Target | Organism | Actions |
|---|---|---|
| Progesterone receptor | Humans | agonist |
| Androgen receptor | Humans | agonist |
| Glucocorticoid receptor | Humans | agonist |
ADME / PK
| Absorption | The C<sub>max</sub> of norethisterone following oral administration of a single dose ranges from 5.39 to 7.36 ng/mL with a T<sub>max</sub> of 1-2 hours. AUC<sub>0-24</sub> values following single oral doses range from approximately 30 to 37 ng*hr/mL. The oral bioavailability of norethisterone is approximately 64%. When applied transdermally, norethisterone is well-absorbed through the skin, reaches steady-state concentrations within 24 hours, and has a C<sub>max</sub> ranging from 617 to 1060 pg/mL at steady state. Norethisterone is often formulated as norethisterone acetate, which is completely and rapidly deacetylated to norethisterone following oral administration - the disposition of norethisterone acetate is indistinguishable from that of orally administered norethisterone. |
|---|---|
| Half-life | The half-life of norethisterone has been variably estimated as 8-10 hours. |
| Protein binding | Norethisterone is 38% bound to sex hormone-binding globulin and 61% bound to albumin. |
| Metabolism | Norethisterone is extensively metabolized, primarily in the liver, to a number of metabolites via partial and total reduction of its A-ring. The enzymes predominantly involved are 3α- and 3β-hydroxysteroid dehydrogenase (HSD) as well as 5α- and 5β-reductase. The 5α-reduced metabolites, including 5α-dihydronorethisterone and its derivatives, appear to carry biological activity while the 5β-reduced metabolites appear inactive. Norethisterone and its metabolites are also extensively conjugated - most of the plasmatic metabolites are sulfate conjugates, while most of the urinary metabolites are glucuronide conjugates. The major metabolites in plasma are a disulfate conjugate of 3α,5α-tetrahydronorethisterone and a monosulfate conjugate of 3α,5β-tetrahydronorethisterone, while the major metabolite(s) in the urine are comprised of glucuronide and/or sulfate conjugates of 3α,5β-tetrahydronorethisterone. Norethisterone has also been observed to undergo some degree of metabolism via the cytochrome P450 enzyme system, predominantly by CYP3A4 and, to a much lesser extent, by CYP2C19, CYP1A2, and CYP2A6. The metabolites generated by these reactions have not been fully characterized. |
| Route of elimination | Following administration of radio-labeled norethisterone, slightly more than 50% of the administered dose was eliminated in the urine and 20-40% was eliminated in the feces. |
| Volume of distribution | The volume of distribution of norethisterone is approximately 4 L/kg. Sulfated metabolites of norethisterone, as well as small quantities of parent drug, have been shown to distribute into breast milk. |
| Clearance | The plasma clearance of norethisterone has been estimated as 0.4 L/hr/kg, and the intrinsic clearance is approximately 73-81 L/h. |
Formulation & handling
- Norethisterone is a small molecule steroid primarily formulated for oral administration, with additional parenteral (intramuscular) and transdermal routes available.
- The compound exhibits low water solubility and moderate lipophilicity (LogP 3.22), which may influence formulation strategies for bioavailability enhancement.
- Administration can occur with or without food, as food intake does not significantly impact its pharmacokinetics.
Regulatory status
| Lifecycle | The active pharmaceutical ingredient is available in markets including the US, Canada, and the EU, with key patent protections in the US expiring between 2016 and 2021, while one patent remains active until 2029, indicating a partially mature market with ongoing patent coverage. |
|---|
| Markets | US, Canada, EU |
|---|
Supply Chain
| Supply chain summary | The manufacturing landscape for Norethisterone includes multiple originator and generic manufacturers, reflecting a diversified supply base. Branded products such as Activella have a presence across the US, Canada, and EU markets. Patent data indicates that while some patents have recently expired or will soon expire, others remain valid until 2029, suggesting a coexistence of established generics alongside ongoing patent-protected branded formulations. |
|---|
Safety
| Toxicity | The oral LD<sub>50</sub> in mice 6 g/kg and the TDLo in human women is 42 mg/kg. There have been no reports of serious ill effects following overdose of oral contraceptives, including following ingestion by children. Symptoms of overdosage are likely to be consistent with the adverse effect profile of the contraceptive and may, therefore, include significant nausea and/or vomiting. |
|---|
- Oral LD50 in mice is 6 g/kg
- Human TDLo reported at 42 mg/kg
- Overdose symptoms may include nausea and vomiting consistent with known adverse effects
Norethisterone is a type of Progestagens
Progestagens are a subcategory of pharmaceutical active pharmaceutical ingredients (APIs) that play a crucial role in hormonal therapies and contraceptives. Also known as progestins, these synthetic compounds mimic the effects of the naturally occurring hormone progesterone in the body.
Progestagens are widely used in various medical applications due to their ability to regulate the menstrual cycle, support pregnancy, and prevent undesired conception. They function by binding to progesterone receptors and modulating the reproductive system's activity.
In addition to their contraceptive properties, progestagens are utilized in hormone replacement therapy (HRT) to alleviate symptoms associated with menopause, such as hot flashes and mood swings. They can also be prescribed to treat irregular menstruation, endometriosis, and certain types of cancer, including breast and uterine cancers.
Pharmaceutical companies develop progestagens in different formulations, including oral tablets, injections, and implants, to cater to diverse patient needs. These formulations offer varying durations of action, allowing healthcare professionals to tailor treatment regimens to individual patients.
While progestagens are generally well-tolerated, they may be associated with certain side effects, such as weight gain, bloating, and breast tenderness. It is essential for healthcare providers to assess patient medical history and monitor their response to progestagen therapy closely.
In conclusion, progestagens are a vital class of pharmaceutical APIs with significant therapeutic applications. Their versatility and effectiveness in hormonal regulation make them a cornerstone of various hormonal therapies, providing patients with safe and reliable options for contraception, HRT, and managing reproductive disorders.
Norethisterone (Progestagens), classified under Hormonal Agents
Hormonal agents are a prominent category of pharmaceutical active pharmaceutical ingredients (APIs) widely used in the medical field. These substances play a crucial role in regulating and modulating hormonal functions within the body. Hormonal agents are designed to mimic or manipulate the effects of naturally occurring hormones, allowing healthcare professionals to treat various endocrine disorders and hormonal imbalances.
Hormonal agents are commonly employed in the treatment of conditions such as hypothyroidism, hyperthyroidism, diabetes, and hormonal cancers. These APIs work by interacting with specific hormone receptors, either by stimulating or inhibiting their activity, to restore the balance of hormones in the body. They can be administered orally, intravenously, or through other routes depending on the specific medication and patient needs.
Pharmaceutical companies employ rigorous manufacturing processes and quality control measures to ensure the purity, potency, and safety of hormonal agent APIs. These APIs are synthesized using chemical or biotechnological methods, often starting from natural hormone sources or through recombinant DNA technology. Stringent regulatory guidelines are in place to guarantee the efficacy and safety of hormonal agent APIs, ensuring that patients receive high-quality medications.
As the demand for hormone-related therapies continues to grow, ongoing research and development efforts focus on enhancing the effectiveness and reducing the side effects of hormonal agent APIs. This includes the exploration of novel delivery systems, advanced formulations, and targeted drug delivery methods. By continuously advancing our understanding and capabilities in hormonal agents, the medical community can improve patient outcomes and quality of life for individuals with hormonal disorders.
Norethisterone API manufacturers & distributors
Compare qualified Norethisterone API suppliers worldwide. We currently have 10 companies offering Norethisterone API, with manufacturing taking place in 5 different countries. Use the table below to review supplier type, countries of origin, certifications, product portfolio and GMP audit availability.
| Supplier | Type | Country | Product origin | Certifications | Portfolio |
|---|---|---|---|---|---|
| Bayer | Producer | Germany | Unknown | CEP, CoA, GMP, USDMF | 42 products |
| Coral Drugs | Producer | India | India | BSE/TSE, CoA, EDMF/ASMF, FDA, GMP, ISO9001, WC, WHO-GMP | 25 products |
| Flavine | Distributor | Germany | Unknown | CoA | 83 products |
| Gedeon Richter | Producer | Hungary | Hungary | CoA, GMP | 48 products |
| Gonane Pharma | Producer | India | India | BSE/TSE, CoA, GMP, MSDS | 166 products |
| LGM Pharma | Distributor | United States | World | BSE/TSE, CEP, CoA, GMP, MSDS, USDMF | 441 products |
| Lupin | Producer | India | India | CoA, USDMF | 155 products |
| Symbiotec Pharma | Producer | India | India | CoA, GMP, WC | 50 products |
| Zhejiang Xianju | Producer | China | China | CEP, CoA, FDA, WC | 17 products |
| Zhejiang Xianju Junye | Producer | China | China | CEP, CoA, FDA | 7 products |
When sending a request, specify which Norethisterone API quality you need: for example EP (Ph. Eur.), USP, JP, BP, or another pharmacopoeial standard, as well as the required grade (base, salt, micronised, specific purity, etc.).
Use the list above to find high-quality Norethisterone API suppliers. For example, you can select GMP, FDA or ISO certified suppliers. Visit our help page to learn more about sourcing APIs via Pharmaoffer.
