Norethindrone

Norethindrone (NET), or norethisterone, is a synthetic progestogen derived from testosterone and used in hormonal contraceptives, hormone replacement therapy, and treatment of gynecological disorders. Prodrugs of NET used in medications include norethindrone acetate (NETA) and norethindrone enanthate (NETE).

Tags
Approvals
WHO Prequalification
Related Compounds
Norethindrone Acetate Norethindrone Enanthate
norethisterone
MOL SDF CML

Identifiers

Abbreviation

NET

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References

Names

  • norethisterone
  • 17-hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one
  • ethinylnortestosterone

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References

CASRN

68-22-4

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References

PubChem CID

6230

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References

  1. PubChem: Norethindrone (View all citations for this reference)

ECHA InfoCard

  • 100.000.619
  • EC / List #: 200-681-4

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References

  1. ECHA: Norethisterone (View all citations for this reference)

IUPHAR/BPS

2880

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References

  1. IUPHAR/BPS: Norethisterone (View all citations for this reference)

DrugBank Accession Number

DB00717

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References

  1. DrugBank: Norethisterone
    Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2017 Nov 8. doi: 10.1093/nar/gkx1037     (View all citations for this reference)

UNII

T18F433X4S

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References

  1. UNII: Norethindrone (View all citations for this reference)

KEGG Entry Number

D00182

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References

  1. KEGG: Norethindrone (View all citations for this reference)

Wikipedia Entry Name

Norethisterone

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References

  1. Wikipedia: Norethisterone (View all citations for this reference)

ChEBI ID

CHEBI:7627

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References

  1. ChEBI: Norethisterone (View all citations for this reference)

ChEMBL ID

CHEMBL1162

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References

  1. ChEMBL: Norethisterone (View all citations for this reference)

ChemSpider ID

5994

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References

  1. ChemSpider: Norethindrone (View all citations for this reference)

PDB

NDR

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References

  1. Protein Databank Ligand: Norethindrone. (View all citations for this reference)

NIST

Norethisterone

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References

  1. NIST Chemistry WebBook: Norethindrone. (View all citations for this reference)

ATC Code(s)

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References

  1. ECHA: Norethisterone (View all citations for this reference)

Physical & Chemical Properties

Molecular Formula

C20H26O2

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References

Molecular Weight

298.419 g/mol

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References

Appearance

White or yellowish white, odorless, crystalline powder

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References

  1. British Pharmacopoeia 2014: Norethisterone API
    2. (View all citations for this reference)
  2. British Pharmacopoeia 2017: Norethisterone monograph.
    3. (View all citations for this reference)
  3. WHO International Agency for Research on Cancer: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Volume 91: Combined Estrogen-Progestogen Contraceptives and Combined Estrogen-Progestogen Menopausal Therapy. 2007, Lyon, France. (View all citations for this reference)

Melting Point

Zafar: 201-203 °C
IARC, Toxnet: 203-204 °C

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References

  1. Zafar, S.; Yousuf, S.; Kayani, H. A.; Saifullah, S.; Khan, S.; Al-Majid, A. M.; Choudhary, M. I. Biotransformation of Oral Contraceptive Ethynodiol Diacetate with Microbial and Plant Cell Cultures. Chem. Cent. J. 2012, 6 (1), 452. (View all citations for this reference)
  2. WHO International Agency for Research on Cancer: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Volume 91: Combined Estrogen-Progestogen Contraceptives and Combined Estrogen-Progestogen Menopausal Therapy. 2007, Lyon, France. (View all citations for this reference)
  3. Toxnet: Norethindrone. (View all citations for this reference)

Solubility

Insoluble in water, soluble in chloroform and dioxane, sparingly soluble in acetone and anhydrous ethanol. Slightly soluble in diethyl ether.

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References

  1. British Pharmacopoeia 2014: Norethisterone API
    2. (View all citations for this reference)
  2. WHO International Agency for Research on Cancer: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Volume 91: Combined Estrogen-Progestogen Contraceptives and Combined Estrogen-Progestogen Menopausal Therapy. 2007, Lyon, France. (View all citations for this reference)

logP

2.97

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References

  1. Toxnet: Norethindrone. (View all citations for this reference)

Specific Optical Rotation

-32.0 to -37.0 (dried)
-31.7 °C in chloroform

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References

  1. British Pharmacopoeia 2014: Norethisterone API
    2. (View all citations for this reference)
  2. British Pharmacopoeia 2017: Norethisterone monograph.
    3. (View all citations for this reference)
  3. WHO International Agency for Research on Cancer: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Volume 91: Combined Estrogen-Progestogen Contraceptives and Combined Estrogen-Progestogen Menopausal Therapy. 2007, Lyon, France. (View all citations for this reference)

Storage Conditions

Stable in air, unstable when exposed to both air and light.

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References

  1. Toxnet: Norethindrone. (View all citations for this reference)

Toxicology

GHS Hazard Code(s)

Class Category Code Description
Carcinogenicity 2 H351 Suspected of causing cancer if inhaled
Reproductive Toxicity 1A H360FD May damage fertility. May damage the unborn child
Reproductive Toxicity, Effects On or Via Lactation H362 May cause harm to breast-fed children
Acute Dermal Toxicity 4 H312 Harmful in contact with skin
Acute Inhalation Toxicity 4 H332 Harmful if inhaled
Reproductive Toxicity 1B H360 May damage fertility or the unborn child

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References

  1. ECHA: Norethisterone (View all citations for this reference)

Mutagenicity

Not found to be mutagenic in the Ames Salmonella/microsome direct plate incorporation protocol.

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References

  1. Lang, R.; Reimann, R. Studies for a Genotoxic Potential of Some Endogenous and Exogenous Sex Steroids. I. Communication: Examination for the Induction of Gene Mutations Using the Ames Salmonella/microsome Test and the HGPRT Test in V79 Cells. Environ. Mol. Mutagen. 1993, 21 (3), 272–304. (View all citations for this reference)

Genotoxicity

Reports vary: Ahmad et al. reported it as non-genotoxic to human lymphocyte chromosomes as measured by chromosomal aberrations, sister chromatid exchanges, and cell growth kinetics. Martelli et al. suggested it could be a week genotoxin.

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References

  1. Ahmad, M. E.; Shadab, G.; Azfer, M. A.; Afzal, M. Evaluation of Genotoxic Potential of Synthetic Progestins-Norethindrone and Norgestrel in Human Lymphocytes in Vitro. Mutat. Res. Toxicol. Environ. Mutagen. 2001, 494 (1–2), 13–20. (View all citations for this reference)
  2. Martelli, A.; Mereto, E.; Ghia, M.; Orsi, P.; Allavena, A.; De Pascalis, C. R.; Brambilla, G. Induction of Micronuclei and of Enzyme-Altered Foci in the Liver of Female Rats Exposed to Progesterone and Three Synthetic Progestins. Mutat. Res. Toxicol. Environ. Mutagen. 1998, 419 (1–3), 33–41. (View all citations for this reference)

LD50

LD50, mouse oral: 6 g/kg
TDLo, human women oral: 42 mg/kg

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References

  1. ChemIDPlus: A Toxnet Database. Norethindrone. (View all citations for this reference)
  2. Toxnet: Norethindrone. (View all citations for this reference)

MRTD

0.0167 mg/kg/day

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References

  1. DSSTox (FDAMDD) FDA Maximum (Recommended) Daily Dose Database. National Center for Biotechnology Information. PubChem BioAssay Database; AID=1195. (View all citations for this reference)

Biochemistry & Pharmacology

Progesterone Receptor Activity

Agonist

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References

Androgen Receptor Activity

Agonist

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References

  1. Africander, D.; Verhoog, N.; Hapgood, J. P., Molecular mechanisms of steroid receptor-mediated actions by synthetic progestins used in HRT and contraception. Steroids 2011, 76 (7), 636-52.
    2. (View all citations for this reference)
  2. Ruan, X.; Seeger, H.; Mueck, A. O., The pharmacology of nomegestrol acetate. Maturitas 2012, 71 (4), 345-53.
    3. (View all citations for this reference)
  3. Lello, S., Nomegestrol Acetate Pharmacology, Safety Profile and Therapeutic Efficacy. Drugs 2010, 70 (5), 541-559.
    4. (View all citations for this reference)
  4. Kuhl, H., Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric 2005, 8 Suppl 1, 3-63.
    5. (View all citations for this reference)

Estrogen Receptor Activity

Agonist and antagonist

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References

  1. Africander, D.; Verhoog, N.; Hapgood, J. P., Molecular mechanisms of steroid receptor-mediated actions by synthetic progestins used in HRT and contraception. Steroids 2011, 76 (7), 636-52.
    2. (View all citations for this reference)
  2. Kuhl, H., Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric 2005, 8 Suppl 1, 3-63.
    3. (View all citations for this reference)
  3. Ruan, X.; Seeger, H.; Mueck, A. O., The pharmacology of nomegestrol acetate. Maturitas 2012, 71 (4), 345-53.
    4. (View all citations for this reference)
  4. Lello, S., Nomegestrol Acetate Pharmacology, Safety Profile and Therapeutic Efficacy. Drugs 2010, 70 (5), 541-559.
    5. (View all citations for this reference)

Glucocorticoid Receptor Activity

No activity

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References

  1. Africander, D.; Verhoog, N.; Hapgood, J. P., Molecular mechanisms of steroid receptor-mediated actions by synthetic progestins used in HRT and contraception. Steroids 2011, 76 (7), 636-52.
    2. (View all citations for this reference)
  2. Kuhl, H., Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric 2005, 8 Suppl 1, 3-63.
    3. (View all citations for this reference)
  3. Ruan, X.; Seeger, H.; Mueck, A. O., The pharmacology of nomegestrol acetate. Maturitas 2012, 71 (4), 345-53.
    4. (View all citations for this reference)
  4. Lello, S., Nomegestrol Acetate Pharmacology, Safety Profile and Therapeutic Efficacy. Drugs 2010, 70 (5), 541-559.
    5. (View all citations for this reference)

Mineralocorticoid Receptor Activity

No activity

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References

  1. Kuhl, H., Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric 2005, 8 Suppl 1, 3-63.
    2. (View all citations for this reference)
  2. Ruan, X.; Seeger, H.; Mueck, A. O., The pharmacology of nomegestrol acetate. Maturitas 2012, 71 (4), 345-53.
    3. (View all citations for this reference)
  3. Lello, S., Nomegestrol Acetate Pharmacology, Safety Profile and Therapeutic Efficacy. Drugs 2010, 70 (5), 541-559.
    4. (View all citations for this reference)

Target Pathways

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References

  1. KEGG: Norethindrone (View all citations for this reference)

Bioavailability

64%

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References

  1. Stanczyk, F. Z., Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception. Rev. Endocr. Metab. Disord. 2002, 3 (3), 211-224. (View all citations for this reference)

Elimination Half-Life (t1/2)

7-8 h (Stanczyk, Goodman & Gilman)
4.8 - 12.8 h (Toxnet)

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References

  1. Stanczyk, F. Z.; Archer, D. F.; Bhavnani, B. R., Ethinyl estradiol and 17 beta-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment. Contraception 2013, 87 (6), 706-727.
    2. (View all citations for this reference)
  2. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e, 2011 > Estrogens and Progestins. Laurence L. Brunton, Bruce A. Chabner, Björn C. Knollmann.
    3. (View all citations for this reference)
  3. Toxnet: Norethindrone. (View all citations for this reference)

Serum Protein Binding

> 95%, 61% to albumin, 36% to SHBG

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References

  1. Kuhl, H., Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric 2005, 8 Suppl 1, 3-63.
    2. (View all citations for this reference)
  2. Nilsson, B.; von Schoultz, B., Binding of levonorgestrel, norethisterone and desogestrel to human sex hormone binding globulin and influence on free testosterone levels. Gynecol Obstet Invest 1989, 27 (3), 151-4. (View all citations for this reference)
  3. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e, 2011 > Estrogens and Progestins. Laurence L. Brunton, Bruce A. Chabner, Björn C. Knollmann.
    4. (View all citations for this reference)
  4. Toxnet: Norethindrone. (View all citations for this reference)

Metabolism

CYP3A4

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References

  1. Nanda, K.; Stuart, G. S.; Robinson, J.; Gray, A. L.; Tepper, N. K.; Gaffield, M. E. Drug Interactions between Hormonal Contraceptives and Antiretrovirals. AIDS 2017, 31 (7), 917–952. (View all citations for this reference)

Apparent Volume of Distribution

4 L/kg

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References

  1. Toxnet: Norethindrone. (View all citations for this reference)

Clearance

0.4 L/h/kg

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References

  1. Toxnet: Norethindrone. (View all citations for this reference)

Enzyme Interactions

Estrone sulfatase inhibitor

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References

  1. Pasqualini, J. R. The Selective Estrogen Enzyme Modulators in Breast Cancer: A Review. Biochim. Biophys. Acta - Rev. Cancer 2004, 1654 (2), 123–143. (View all citations for this reference)

Inhibition of Ovulation

0.5 mg/day

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References

  1. Rebar, R. W.; Zeserson, K., CHARACTERISTICS OF THE NEW PROGESTOGENS IN COMBINATION ORAL-CONTRACEPTIVES. Contraception 1991, 44 (1), 1-10.
    2. (View all citations for this reference)

Transformation of Endometrium

100-150 mg/cycle

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References

  1. Rebar, R. W.; Zeserson, K., CHARACTERISTICS OF THE NEW PROGESTOGENS IN COMBINATION ORAL-CONTRACEPTIVES. Contraception 1991, 44 (1), 1-10.
    2. (View all citations for this reference)

Menstrual Delay

10-15 mg/day

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References

  1. Rebar, R. W.; Zeserson, K., CHARACTERISTICS OF THE NEW PROGESTOGENS IN COMBINATION ORAL-CONTRACEPTIVES. Contraception 1991, 44 (1), 1-10.
    2. (View all citations for this reference)

Indications

Menopause

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References

  1. ChEMBL: Norethisterone (View all citations for this reference)

Metabolites

Name
Structure
Notes
Other Norethindrone Metabolites

Sulfate and glucuronide conjugates of norethindrone and its metabolites are also present.

19-Norandrosterone
structure

The epimer 19-noretiocholanolone may also be formed by metabolism of NET. Detection of 19-norandrosterone in an athlete's urine is taken as evidence of doping by nandrolone or another 19-steroid. However, this compound is a metabolite of norethindrone, and as a metabolite, it can be detected in quantities above the reporting threshold of 2 ng/mL.

5α-Dihydronorethindrone
structure

Major metabolite.

5β-Dihydronorethindrone
structure

3β,5β-Tetrahydronorethindrone
structure

View All (10)

Impurities

Name
Structure
CASRN
Other Names & Identifiers
6α-Hydroxynorethisterone
structure

Norethindrone Dimer
structure

  • Impurity 4 (Gorog 1987)

17α-Ethynyl-17-hydroxy-4-oestrene-3,6-dione
structure

  • Impurity 1 (Gorog 1987)

6β-Hydroxynorethisterone
structure

  • BP Norethisterone Impurity H
  • 6β,17-dihydroxy-19-nor-17α-pregn-4-en-20-yn-3-one

17-Epi-Norethisterone
structure

  • BP Norethisterone Impurity G
  • 17-hydroxy-19-norpregn-4-en-20-yn-3-one
  • Impurity 3 (Gorog 1987)

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US FDA-Approved Products

Name
Formulation
Status
ANDA #
Wera
ETHINYL ESTRADIOL: 0.035 mg NORETHINDRONE: 0.5 mg 28 oral tablets

Prescription

091204

Vyfemla
ETHINYL ESTRADIOL: 0.035 mg NORETHINDRONE: 0.4 mg 28 oral tablets

Prescription

201886

Tri-Norinyl 28-Day
ETHINYL ESTRADIOL: 0.035 mg, 0.035 mg, 0.035 mg NORETHINDRONE: 0.5 mg, 1 mg, 0.5 mg 28 oral tablets

Prescription

018977

Tri-Norinyl 21-Day
ETHINYL ESTRADIOL: 0.035 mg, 0.035 mg, 0.035 mg NORETHINDRONE: 0.5 mg, 1 mg, 0.5 mg 21 oral tablets

Discontinued

018977

Tri-Legest FE
ETHINYL ESTRADIOL: 0.02 mg, 0.03 mg, 0.035 mg
NORETHINDRONE: 1 mg, 1 mg, 1 mg
28 oral tablets

Prescription

076105

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WHO Prequalified Medicine

WHO Reference #
Name
Applicant
Formulation
RH045 (a)
Norethindrone
Lupin LTD
350 μg, tablet
RH043 (a)
Norethindrone
Lupin LTD
350 μg, tablet
[Listed as NORETHISTERONE]
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