Norethisterone

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Structural formula
Structure of norethisterone
General
Non-proprietary name Norethisterone
other names
  • 17 β- hydroxy-19-nor-17 α -pregn-4-en-20-in-3-one ( IUPAC )
  • Norethindrone
Molecular formula C 20 H 26 O 2
External identifiers / databases
CAS number 68-22-4
EC number 200-681-6
ECHA InfoCard 100,000,619
PubChem 6230
ChemSpider 5994
DrugBank DB00717
Wikidata Q421352
Drug information
ATC code
Drug class

Progestins

properties
Molar mass 298.42 g · mol -1
Physical state

firmly

Melting point

203-204 ° C

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
08 - Dangerous to health

Caution

H and P phrases H: 351
P: 281
Toxicological data

> 6000 mg kg −1 ( LD 50 ,  mouse ,  oral )

As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Norethisterone (also norethindrone ) is a drug from the group of synthetically produced luteal hormones (progestins) of the 1st generation. Norethisterone is used for contraception - mostly in combination with an estrogen ( birth control pill ), but also alone ( minipill , three-month injection ). It is also a component of drugs for the treatment of menopausal symptoms ( postmenopausal hormone replacement treatment ).

history

Norethisterone was the first orally active synthetic progestin.

It was first synthesized in 1951 by Carl Djerassi , Luis E. Miramontes and George Rosenkranz at Syntex in Mexico City .

In addition to its use in contraception, norethisterone was used in high doses in combination with ethinylestradiol until 1978 under the brand name Duogynon and until 1981 under the name Cumorit as a pregnancy test and for the treatment of menstrual disorders (secondary amenorrhea) and - as can be deduced from the feminist women's literature of the 1970s - Probably also improperly as an abortive drug (drug used to terminate pregnancy), then used in overdosing (4 or 6 tablets of Duogynon instead of the usual 2 tablets).

Duogynon scandal

Schering sold a hormone agent in two forms of administration (tablets and injection ampoules) in the Federal Republic of Germany until 1978 under the brand name Duogynon and until 1981 under the name Cumorit . Duogynon, taken in early pregnancy, was already associated with an increase in malformed children in 1967.

Chemical-pharmaceutical information

Norethisterone is a derivative of nortestosterone . In contrast to progesterone , the ethynyl group introduced at C-17 makes it effective orally . In addition to norethisterone itself, its esters of acetic acid (norethisterone acetate) and enanthic acid (norethisterone enanthate ) are used medicinally .

Pharmacological properties

The effects of norethisterone correspond largely - but not in all properties - to those of progesterone , that is, norethisterone promotes the growth of the uterine muscles and the milk cells in the breasts. The synthesized substance inhibits the cell proliferation of the uterine lining and promotes its secretion phase . Norethisterone causes the mucus formed on the uterus cervix to become more viscous and thus impenetrable for sperm. It inhibits the release of luteinizing hormone (LH) from the anterior lobe of the pituitary gland ( adenohypophysis ) and thereby suppresses ovulation .

Because of its structural relationship with nortestosterone, norethisterone also has an androgenic effect.

Norethisterone and norethisterine acetate are rapidly absorbed from the gastrointestinal tract . The ester compound is rapidly hydrolyzed, producing the pharmacologically active norethisterone. The plasma half-life is 4 to 13 hours.

The additional ethynyl group at C-17 influences the pharmacokinetic properties in particular : for example, compared to progesterone, norethisterone has a reduced first-pass effect in the liver, resulting in a significantly increased oral bioavailability. To what extent, due to the reduced breakdown of the substance in the human or also in the animal organism, an accumulation of the medicinal substance takes place is largely unclear.

Clinical information

Norethisterone / norethisterone acetate is often used in combination with an estrogen, for example in doses of 0.5 to 1 mg for hormonal contraception and in doses of 1 to 2 mg in hormone replacement therapy. Norethisterone is also used for contraception as a monopreparation in doses of 0.35 mg in the "mini pill" and with 200 mg norethisterone enanthate in the three-month syringe, an oily injection depot for intramuscular use.

Other areas of application for norethisterone include dysfunctional bleeding, endometriosis, and advanced breast or uterine cancer.

Contraindications for treatment with norethindrone are primarily how to treat with other progestins also thrombo embolic disease, severe liver dysfunction and hyperbilirubinemia . Because of the risk of masculinization ( masculinization ) female fetuses is contraindicated in pregnancy norethindrone.

Side effects can include nausea and vomiting, headaches, skin rashes, depressive moods and a feeling of tension in the breasts. Decreased libido and weight gain can also occur as a result of treatment with norethisterone.

Trade names

Monopreparations

Micronovum (A, CH), Noristerat (D), Primolut (CH) and generics

Combination preparations

Activelle (D, A, CH), Clionara (D), Cliovelle (D), Duogynon (D), Duokliman (A), Estalis (D, A, CH), Estracomb (A, CH), Estragest (D, CH ), Estranor (CH), EVE (D), Gynamon (D), Kliogest (D, A, CH), Mericomb (D, A, CH), Merigest (D, A, CH), Novofem (D, CH) , Ovysmen (A), Perikliman (A), Primodos (GB), Primosiston (A, CH), Sequidot (D, A, CH), Systen (CH), Trinovum (A, CH), Trissequence (A, CH) , Conceplan M (D)

Web links

On Schering's Duogynon scandal in Germany:

For the British investigation of Schering's Primodos pregnancy test  :

Documentary film

Individual evidence

  1. ^ The Merck Index . An Encyclopaedia of Chemicals, Drugs and Biologicals. 14th edition. 2006, ISBN 0-911910-00-X , p. 1157.
  2. ↑ a b Data sheet 19-Norethindrone from Sigma-Aldrich , accessed on April 16, 2011 ( PDF ).
  3. ↑ Data sheet NORETHISTERONE CRS (PDF) at EDQM , accessed on August 2, 2008.
  4. ↑ C. Djerassi, L. Miramontes, G. Rosenkranz, F. Sondheimer: Steroids. LIV. Synthesis of 19-Nor-17α-ethynyltestosterone and 19-Nor-17α-methyltestosterone . In: J Am Chem Soc . tape 76 , no. 16 , 1954, pp. 4089-4091 , doi : 10.1021 / ja01645a010 .
  5. ↑ G. Tümmler, C. Schaefer: Duogynon: Congenital malformations after application of the estrogen-progesterone combination in pregnancy - evaluation of a retrospective case series. Retrieved March 18, 2020 . In: Bulletin on drug safety. Federal Institute for Drugs and Medical Devices and Paul Ehrlich Institute , Issue 4, December 2012, pp. 20–23.
  6. ↑ a b c E. Mutschler, G. Geisslinger, HK Kroemer, P. Ruth, M. Schäfer-Korting: drug effects. Textbook of pharmacology and toxicology. 9th edition. Wissenschaftliche Verlagsgesellschaft, Stuttgart 2008, ISBN 978-3-8047-1952-1 , p. 453.
  7. ↑ a b c d e K. Hardtke u. a. (Ed.): Commentary on the European Pharmacopoeia Ph. Eur. 4.0, cortisone acetate. Loose-leaf collection, 25th delivery 2006, Wissenschaftliche Verlagsgesellschaft, Stuttgart.

literature

  • Eckart Roloff and Karin Henke-Wendt: Duogynon - again Contergan, but almost secret? In: dies., Damaged instead of cured. Major German medical and pharmaceutical scandals. Hirzel, Stuttgart 2018, pp. 49–63, ISBN 978-3-7776-2763-2 .