Clomiphene

Structural formula
Mixture of ( E ) isomer (top) and ( Z ) isomer (bottom)
General
Non-proprietary name	Clomiphene
other names	( E , Z ) - {2- [4- (2-chloro-1,2-diphenylvinyl) phenoxy] ethyl} diethylamine ( E ) - {2- [4- (2-chloro-1,2-diphenylvinyl) phenoxy] ethyl} diethylamine ( Z ) - {2- [4- (2-Chloro-1,2-diphenylvinyl) phenoxy] ethyl} diethylamine trans - {2- [4- (2-chloro-1,2-diphenylvinyl) phenoxy] ethyl} diethylamine cis - {2- [4- (2-chloro-1,2-diphenylvinyl) phenoxy] ethyl} diethylamine
Molecular formula	C 26 H 28 ClNO [( E, Z ) -clomifene] C 26 H 28 ClNO · C 6 H 8 O 7 [( E, Z ) -clomifene · citrate]
Brief description	Crystals [( E, Z ) -clomifene · citrate]
External identifiers / databases
CAS number 911-45-5 [( E, Z ) -clomifene] 50-41-9 [( E, Z ) -clomifene · citrate ] 15690-55-8 [ cis -clomifene · hydrochloride ] 15690-57-0 [ trans -clomifene · hydrochloride] EC number 213-008-6 ECHA InfoCard 100,011,826 PubChem 2800 ChemSpider 2698 DrugBank DB00882 Wikidata Q418730
Drug information
ATC code	G03 GB02
Drug class	Selective estrogen receptor modulator
properties
Molar mass	405.97 g · mol -1 [( E, Z ) -Clomifen] 598.08 g · mol -1 [( E, Z ) -Clomifen · citrate]
Melting point	116.5-118 ° C [( E, Z ) -clomifene · citrate] 156.5–158 ° C [ cis -clomifene · hydrochloride] 149.0–150.5 ° C [ trans -clomifene hydrochloride]
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances Caution H and P phrases H: 361 P: 281
Toxicological data	390 mg kg −1 ( LD 50 ,  mouse ,  ip ) 1700 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 .

Clomiphene (also clomiphene ) is a drug from the group of selective estrogen receptor modulators (SERM). He is shown to trigger an ovulation ( ovulation ) in women with infertility and for the treatment of certain forms of a lack of menstruation ( amenorrhea ).

In hypogonadal men, clomiphene increases testosterone production .

effect

The main reason for the effect is that the gonadotropin- producing cells in the pituitary gland ( pituitary gland ) are simulated to have a lack of sex hormones. It is believed that the stilbene derivative clomiphene binds to the steroid receptor in the hypothalamus and blocks it for the corresponding steroid ( testosterone or estrogen ). As a result, the gonadotropin producing cells release more LH and FSH in order to raise the (apparently too low) level of sex hormones. This leads to the stimulation of ovarian or testicular function . Since the inhibition is competitive , the desired sex hormone level can be set quite precisely with the Clomifendose. The prerequisite for effectiveness is the functionality of the pituitary and gonads.

In addition to the hypothalamus, clomiphene develops its estrogen-agonistic or antagonistic effects on other organs ( cervix , uterine lining , follicles ). It should also directly stimulate the estrogen synthesis in the follicle. Clomiphene has no gestagenic , androgenic , antiandrogenic or gluco- and mineralocorticoid effects. Clomiphene also acts as a FIASMA (functional inhibitor of acid sphingomyelinase ).

Multiple pregnancies can occur more frequently during fertility treatment with clomiphene.

As an estrogen antagonist , which by stimulating the secretion of FSH and LH not only increases the activity of the female but also the male gonads and could have a positive effect on spermatogenesis , the use of clomiphene for the treatment of men who wish to have children is conceivable. The use of estrogen antagonists for the treatment of idiopathic infertility in men was examined in a meta-analysis. Studies suggest that they can increase sperm concentration, percent sperm motility, and the spontaneous pregnancy rate.

abuse

In the sports scene, clomiphene, along with other antiestrogens, is misused to reduce the negative effects of anabolic steroids . Clomiphene is on the World Anti-Doping Agency (WADA) prohibited list .

Isomerism

With regard to its chemical structure, the drug clomiphene is a mixture of the ( E ) and ( Z ) isomers ( cis - trans isomerism ). The antiestrogenic effect of the ( E ) isomer ( enclomiphene ) is clinically relevant , its estrogenic effect is only weak. The ( Z ) isomer ( zuclomiphene ), on the other hand, only has estrogenic activity. The pharmacopoeia limits the content of zuclomifene in the medicinal substance to 30–50%.

Isomerically pure enclomifene was developed for the treatment of underactive gonads in men (secondary hypogonadism ) and an associated non-insulin-dependent diabetes ( type 2 diabetes mellitus ), although approval for the EU was rejected in April 2018.

Pharmaceutical information

Clomiphene citrate is used medicinally . The white to light yellow crystalline powder is light-sensitive and sparingly soluble in water. Clomiphene citrate is effective when given orally .

Trade names

In Germany, the original preparation Dyneric is no longer sold, generics are on the market. The substance is approved as a Clomid in the USA, UK and Canada, for example.

Individual evidence

1. ^ ^{A b c} The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals , 14th Edition (Merck & Co., Inc.), Whitehouse Station, NJ, USA, 2006; P. 2390, ISBN 978-0-911910-00-1 .
2. ↑ ^{a b} entry on clomiphene. In: Römpp Online . Georg Thieme Verlag, accessed on December 25, 2014.
3. ↑ ^{a b} Data sheet Clomiphene citrate salt from Sigma-Aldrich , accessed on March 23, 2011 ( PDF ).
4. ↑ Entry on clomiphene in the ChemIDplus database of the United States National Library of Medicine (NLM) .
5. ^ Katz DJ, ea: Outcomes of clomiphene citrate treatment in young hypogonadal men. In: BJU Int . 2012; 110: 573-578. doi: 10.1111 / j.1464-410X.2011.10702.x . PMID 22044663
6. ↑ Kornhuber J, Muehlbacher M, Trapp S, Pechmann S, Friedl A, Reichel M, Mühle C, Terfloth L, Groemer T, Spitzer G, Liedl K, Gulbins E, Tripal P: Identification of Novel Functional Inhibitors of Acid Sphingomyelinase . In: PLoS ONE . 6, No. 8, 2011, p. E23852. doi : 10.1371 / journal.pone.0023852 .
7. ↑ Ernst Mutschler, Gerd Geisslinger, Heyo K. Kroemer , Sabine Menzel, Peter Ruth: Mutschler drug effects. Pharmacology - Clinical Pharmacology - Toxicology. 10th edition. Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart 2012, ISBN 3-80-472898-7 . P. 418 f.
8. ↑ DocCheck News: Desire for children: Lottchen trend in Germany . May 31, 2016.
9. ↑ ME Chua et al .: Revisiting oestrogen antagonists (clomiphene or tamoxifen) as medical empiric therapy for idiopathic male infertility: a meta-analysis. Andrology. 2013 Sep; 1 (5): 749-57. doi : 10.1111 / j.2047-2927.2013.00107.x .
10. ↑ antiestrogens
11. ↑ WADA 2012 Prohibited List (clomiphene) ( Memento of October 12, 2011 in the Internet Archive ) (PDF; 112 kB), p. 5.
12. ↑ Hermann J. Roth, Christa E. Müller, Gerd Folkers: Stereochemie und Arzneimittel, Wissenschaftliche Verlagsgesellschaft Stuttgart, 1998, p. 111, ISBN 3-8047-1485-4 .
13. ↑ ^{a b} Data sheet Clomifene citrate (PDF) at EDQM , accessed on June 11, 2011.
14. ↑ reproductions Therapeutics Inc., Androxal , accessed on 2 February 2011th
15. ↑ EMA: No approval recommendation for enclomifene on January 26, 2018
16. ↑ Rejected human medicinal products in the EU community register ec.europa.eu, retrieved from the archive on September 26, 2019.

This article is about a health issue. It is not used for self-diagnosis and does not replace a diagnosis by a doctor. Please note the information on health issues !