clomiphene citrate

• クエン酸クロミフェン

関

clomifene、clomifene citrate、clomiphene、enclomiphene

WordNet

1. a salt or ester of citric acid
2. cause to form a salt or ester of citric acid
3. a fertility drug (trade name Clomid) that is used to stimulate ovulation and that has been associated with multiple births (同)clomiphene_citrate, Clomid

PrepTutorEJDIC

1. クエン酸塩

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/02/26 21:06:36」(JST)

wiki en

[Wiki en表示]

Not to be confused with clonidine or Klonopin.

Clomifene

Systematic (IUPAC) name
(E,Z)-2-(4-(2-chloro-1,2-diphenylethenyl) phenoxy)-N,N-diethyl-ethanamine
Clinical data
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Pregnancy category	B3 (Au), X (U.S.)
Legal status	S4 (Au), POM (UK), ℞-only (U.S.)
Routes	per os
Pharmacokinetic data
Bioavailability	High (>90%)
Metabolism	Hepatic (with enterohepatic circulation)
Half-life	5-7 days
Excretion	Mainly renal, some biliary
Identifiers
CAS number	911-45-5 Y
ATC code	G03GB02
PubChem	CID 2800
DrugBank	DB00882
ChemSpider	2698 Y
UNII	1HRS458QU2 Y
KEGG	D07726 Y
ChEBI	CHEBI:3752 Y
ChEMBL	CHEMBL1200667 N
Chemical data
Formula	C26H28ClNO
Molecular mass	406 or 598.10 (with citrate)
SMILES Cl/C(c1ccccc1)=C(/c2ccc(OCCN(CC)CC)cc2)c3ccccc3
InChI InChI=1S/C26H28ClNO/c1-3-28(4-2)19-20-29-24-17-15-22(16-18-24)25(21-11-7-5-8-12-21)26(27)23-13-9-6-10-14-23/h5-18H,3-4,19-20H2,1-2H3 Y Key:GKIRPKYJQBWNGO-UHFFFAOYSA-N Y
N (what is this?)  (verify)

Clomifene (INN) or clomiphene (USAN) (trademarked as Androxal, Clomid and Omifin, citrate salt Serophene) is a selective estrogen receptor modulator (SERM) that has become the most widely prescribed drug for ovulation induction to reverse anovulation or oligoovulation.

Use in anovulation

Clomifene is useful in those who are infertile due to anovulation or oligoovulation. Evidence is lacking for the use of clomifene in those who are infertile without a known reason. In such cases, studies have observed a clinical pregnancy rate 5.6% per cycle with clomifene treatment vs. 1.3%–4.2% per cycle without treatment.

Clomifene has also been used with other assisted reproductive technology to increase success rates of these other modalities.

Clomid can be initiated at a dose of 50 mg daily for 5 days, starting on cycle day 3, 4, or 5 (where cycle day 1 is the first day of the menstrual period), thus being taken on cycle days 3-7, 4-8 or 5-9. During a clomifene-induced cycle, there should be frequent intercourse (every other day) the week before and including the estimated day of ovulation, (cycle days 9-18). If LH surge detection tests are used, these tests should be started 3 to 4 days after the last clomifene tablet is taken (that is, if taking clomifene on cycle days 4-8, LH surge tests should be started on cycle day 11) and continue until ovulation is indicated (that is, the test becomes positive.) or through cycle day 18. If there is no spontaneous surge, there may be an artificial triggering of oocyte release if there is an ovarian follicle of over 20 mm in size, such as by an intramuscular injection of 10,000 units of hCG. However, routinely using oocyte release triggering with hCG appears to decrease pregnancy chances compared to frequent monitoring with LH tests.

The following procedures may be used to monitor induced cycles:

• Follicular monitoring with vaginal ultrasound, starting 4-6 days after last pill. Serial transvaginal ultrasound can reveal the size and number of developing follicles. It can also provide presumptive evidence of ovulation such as sudden collapse of the preovulatory follicle, and an increase in fluid volume in the rectouterine pouch. After ovulation, it may reveal signs of luteinization such as loss of clearly defined follicular margins and appearance of internal echoes.
• Serum estradiol levels, starting 4-6 days after last pill
• Post-coital test 1-3 days before ovulation to check whether there are at least 5 progressive sperm per HPF
• Adequacy of LH surge by urine LH surge tests 3 to 4 days after last clomifene pill
• Mid-luteal progesterone, with at least 10 ng/ml 7-9 days after ovulation being regarded as adequate.

Repeat dosing: This 5-day treatment course can be repeated every 30 days. The dosage may be increased by 50-mg increments in subsequent cycles until ovulation is achieved. It is not recommended by the manufacturer to use clomifene for more than 6 cycles.

It is no longer recommended to perform an ultrasound examination to exclude any significant residual ovarian enlargement before each new treatment cycle.

Adverse events

The most common adverse drug reaction associated with the use of clomifene (>10% of people) is reversible ovarian enlargement. Less common effects (1-10% of people) include visual symptoms (blurred vision, double vision, floaters, eye sensitivity to light, scotomata), headaches, vasomotor flushes (or hot flashes), abnormal uterine bleeding and/or abdominal discomfort. Rare adverse events (<1% of people) include: high blood level of triglycerides, liver inflammation, reversible baldness and/or ovarian hyperstimulation syndrome.

Clomifene can lead to multiple ovulation, hence increasing the chance of twins (10% of births instead of ~1% in the general population) and triplets.

Some studies have suggested that clomifene citrate if used for more than a year may increase the risk of ovarian cancer. This may only be the case in those who have never been and do not become pregnant. Subsequent studies have failed to corroborate those findings. This however is disputed and some feel there is no significant increase in risk.

The incidence of fetal and neonatal abnormalities for patients on clomifene for fertility is similar to that seen in the general population. There is no data to suggest a higher rate of congenital anomalies or spontaneous abortions after using this drug.

Mechanism of action

Clomifene inhibits estrogen receptors in the hypothalamus, inhibiting negative feedback of estrogen on gonadotropin release, leading to up-regulation of the hypothalamic–pituitary–gonadal axis. Zuclomifene, a more active isomer, stays bound for longer periods of time. Clomifene is not a steroid drug.

In normal physiologic female hormonal cycling, at 7 days past ovulation, high levels of estrogen and progesterone produced from the corpus luteum inhibit GnRH, FSH and LH at the hypothalamus and anterior pituitary. If fertilization does not occur in the post-ovulation period the corpus luteum disintegrates due to a lack of beta-hCG. This would normally be produced by the embryo in the effort of maintaining progesterone and estrogen levels during pregnancy.

Therapeutically, clomifene is given early in the menstrual cycle. It is typically prescribed beginning on day 3 and continuing for 5 days. By that time, FSH level is rising steadily, causing development of a few follicles. Follicles in turn produce the estrogen, which circulates in serum. In the presence of clomifene, the body perceives a low level of estrogen, similar to day 22 in the previous cycle. Since estrogen can no longer effectively exert negative feedback on the hypothalamus, GnRH secretion becomes more rapidly pulsatile, which results in increased pituitary gonadotropin (FSH, LH) release. (It should be noted that more rapid, lower amplitude pulses of GnRH lead to increased LH/FSH secretion, while more irregular, larger amplitude pulses of GnRH leads to a decrease in the ratio of LH/FSH.) Increased FSH level causes growth of more ovarian follicles, and subsequently rupture of follicles resulting in ovulation. Ovulation occurs most often 6–7 days after a course of clomifene.

Chemistry

Clomifene is a mixture of two geometric isomers, enclomifene (E-clomifene) and zuclomifene (Z-clomifene). These two isomers have been found to contribute to the mixed estrogenic and anti-estrogenic properties of clomifene.

Enclomifene

Zuclomifene

Off-label use in the treatment of male hypogonadism

Clomifene citrate has been found very effective in the treatment of secondary male hypogonadism in many cases. This has shown to be a much more attractive option than testosterone replacement therapy (TRT) in many cases because of the reduced cost and convenience of taking a pill as opposed to testosterone injections or gels. Unlike traditional TRT it also does not shrink the testes and as a result can enhance fertility. Traditional TRT has the risk of inducing a chemical gonadectomy, although with monitoring and low-dose hCG as adjunct, this is usually preventable and reversible. Because clomifene citrate has not been FDA approved for use in males it is prescribed off-label. Due to the fact that Clomifene is now a generic medication in most markets, it is unlikely that a drug company would pursue FDA approval for use in men now because of limited profit incentive, mostly due to the relatively small market potential. However, the single isomer of clomifene, enclomiphene under the brand name Androxal, is currently under phase 3 trials for use in men.

Non-clinical uses

Clomifene is used by males (especially steroid users at the end of a cycle) to reduce the physical effects caused by high estrogen levels, such as gynecomastia. The drug binds to estrogen receptors to prevent the hormone from binding and therefore taking effect. It also restores the body's natural production of testosterone. It is included on the World Anti-Doping Agency list of illegal doping agents in sport.

History

Clomifene has been used since the 1960s. It was first used to treat cases of oligomenorrhea but was expanded to include treatment of anovulation when women undergoing treatment had higher than expected rates of pregnancy.

In April 1989, a patent was awarded to Yale University Medical researchers Dr. Florence Comite and Dr. Pamela Jensen for the use of clomiphene to predict fertility in women. A woman capable of sustaining pregnancy would develop denser bone mass while on clomiphene; the bone mass increase would be predictive of fertility, and the changes could be detected on a CT scanner.

Synthesis

Clomifene synthesis: Wm S Merrell Co, U.S. Patent 2,914,563 BE 782321 

Clomifene is synthesized from 4-hydroxybenzophenone by reacting it with 2-diethylaminoethylchloride in the presence of an alkali, which gives 4-(2-diethylaminoethoxy)benzophenone. This is reacted with benzylmagnesium chloride in a Grignard reaction, forming as a result the corresponding carbinol, which is dehydrated with HCl. In the last step, the vinylic jydrogen is replaced with a chlorine atom using N-chlorosuccinimide (NCS).

Nitromifene synthesis:

References

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

• 1. クエン酸クロミフェンによる排卵誘発 ovulation induction with clomiphene citrate
• 2. 排卵誘発の概要 overview of ovulation induction
• 3. 排卵誘発におけるクロミフェンの有効性改善の戦略 strategies for improving the efficacy of clomiphene induction of ovulation
• 4. 女性の不妊症の治療の概要 overview of treatment of female infertility
• 5. 女性の不妊評価 evaluation of female infertility

English Journal

• Antiinfectives targeting enzymes and the proton motive force.

• Feng X1, Zhu W1, Schurig-Briccio LA2, Lindert S3, Shoen C4, Hitchings R5, Li J1, Wang Y1, Baig N1, Zhou T1, Kim BK1, Crick DC5, Cynamon M4, McCammon JA6, Gennis RB7, Oldfield E8.
• Proceedings of the National Academy of Sciences of the United States of America.Proc Natl Acad Sci U S A.2015 Dec 22;112(51):E7073-82. doi: 10.1073/pnas.1521988112. Epub 2015 Dec 7.
• There is a growing need for new antibiotics. Compounds that target the proton motive force (PMF), uncouplers, represent one possible class of compounds that might be developed because they are already used to treat parasitic infections, and there is interest in their use for the treatment of other d
• PMID 26644565

• Tetracarpidium conophorum ameliorates oxidative reproductive toxicity induced by ethanol in male rats.

• Akomolafe SF1,2,3, Oboh G2, Akindahunsi AA2, Afolayan AJ4.
• BMC complementary and alternative medicine.BMC Complement Altern Med.2015 Dec 18;15(1):439. doi: 10.1186/s12906-015-0960-5.
• BACKGROUND: Tetracarpidium conophorum (Mull. Arg.) Hutch. & Dalz is one of the many medicinal plants used for ages in folklore as male fertility enhancers. The current study evaluates the effect of the plant leaf extract on alcohol - induced reproductive toxicity in male rats.METHODS: Thirty rat
• PMID 26682909

• AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS, AMERICAN COLLEGE OF ENDOCRINOLOGY, AND ANDROGEN EXCESS AND PCOS SOCIETY DISEASE STATE CLINICAL REVIEW: GUIDE TO THE BEST PRACTICES IN THE EVALUATION AND TREATMENT OF POLYCYSTIC OVARY SYNDROME - PART 2.

• Goodman NF, Cobin RH, Futterweit W, Glueck JS, Legro RS, Carmina E.
• Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists.Endocr Pract.2015 Dec;21(12):1415-26. doi: 10.4158/EP15748.DSCPT2.
• EXECUTIVE SUMMARY Polycystic ovary syndrome (PCOS) is recognized as the most common endocrine disorder of reproductive-aged women around the world. This document, produced by the collaboration of the American Association of Clinical Endocrinologists and the Androgen Excess Society aims to highlight
• PMID 26642102

Japanese Journal

• 当科で管理した卵巣過剰刺激症候群の3症例

• 梅澤 奈穂,尹 純奈,常弘 あずさ,大八木 知史,福田 綾,筒井 建紀
• 産婦人科の進歩 71(1), 30-36, 2019
• <p>卵巣過剰刺激症候群（ovarian hyperstimulation syndrome；以下OHSS）は不妊治療に伴い発症する医原性疾患であり，その予防には各症例に個別化した排卵誘発を行うことが重要である．今回われわれは，異なる経過・妊娠転機をたどったOHSS 3症例を経験した．症例1は35歳，1妊1産，前医で多嚢胞性卵巣症候群（polycystic ovary syndrome …
• NAID 130007627112

• Therapeutic effects of oral clomiphene citrate in 2 dogs with low plasma testosterone levels and poor semen quality

• KOBAYASHI Masanori,HORI Tatsuya,KAWAKAMI Eiichi
• Ｔｈｅ　Ｊｏｕｒｎａｌ　ｏｆ　Ｖｅｔｅｒｉｎａｒｙ　Ｍｅｄｉｃａｌ　Ｓｃｉｅｎｃｅ 80(8), 1233-1235, 2018
• … <p>Two dogs with low plasma testosterone (T) levels and poor semen quality were administered one tablet of 12.5 mg clomiphene citrate orally per day at 2-day intervals for 4 weeks. … These results indicate that poor semen quality in dogs with low plasma T level can be improved by oral administration of clomiphene citrate.</p> …
• NAID 130007432219

• Therapeutic effects of oral clomiphene citrate in 2 dogs with low plasma testosterone levels and poor semen quality

• KOBAYASHI Masanori,HORI Tatsuya,KAWAKAMI Eiichi
• Ｔｈｅ　Ｊｏｕｒｎａｌ　ｏｆ　Ｖｅｔｅｒｉｎａｒｙ　Ｍｅｄｉｃａｌ　Ｓｃｉｅｎｃｅ, 2018
• … <p>Two dogs with low plasma testosterone (T) levels and poor semen quality were administered one tablet of 12.5 mg clomiphene citrate orally per day at 2-day intervals for 4 weeks. … These results indicate that poor semen quality in dogs with low plasma T level can be improved by oral administration of clomiphene citrate.</p> …
• NAID 130007399367

Related Links

• Clomiphene Citrate - Clomiphene Citrate .com

Clomiphene Citrate is a powerful SERM used by many steroid users. Designed to treat fertility issues, Clomiphene Citrate is a prime stimulator of natural testosterone.

• Clomid (Clomiphene Citrate) Effects, Infertility Uses, and More

Drug details for Clomiphene citrate for infertility. ... How It Works Clomiphene stimulates the release of hormones needed to cause ovulation. Clomiphene therapy is typically used for 5 consecutive days early in the menstrual cycle ...

---

★リンクテーブル★

リンク元	「clomifene」「enclomiphene」

「clomifene」

　　[★]

クロミフェン

関

clomifene citrate、clomiphene、clomiphene citrate、enclomiphene

「enclomiphene」

　　[★]

エンクロミフェン

関

clomifene、clomiphene、clomiphene citrate