Clomifene citrate
[CAS# 50-41-9]

Identification

• Classification: API >> Hormone and endocrine-regulating drugs >> Gonadotropin
• Name: Clomifene citrate
• Synonyms: 2-(4-[2-Chloro-1,2-diphenylethenyl]phenoxy)-N,N-diethylethanamine citrate
• Molecular Formula: C₂₆H₂₈ClNO^.C₆H₈O₇
• Molecular Weight: 598.08
• CAS Registry Number: 50-41-9
• EC Number: 200-035-3
• SMILES: CCN(CC)CCOC1=CC=C(C=C1)/C(=C(/C2=CC=CC=C2)\Cl)/C3=CC=CC=C3.C(C(=O)O)C(CC(=O)O)(C(=O)O)O

Safety Data

• Hazard Symbols: GHS08 Danger
• Hazard Statements: H360-H361
• Precautionary Statements: P203-P280-P318-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Reproductive toxicity	Repr.	2	H361
Carcinogenicity	Carc.	2	H351
Reproductive toxicity	Repr.	1B	H360
Reproductive toxicity	Repr.	1A	H360
Specific target organ toxicity - single exposure	STOT SE	3	H335
Skin irritation	Skin Irrit.	2	H315
Reproductive toxicity	Repr.	1B	H360Fd
Respiratory sensitization	Resp. Sens.	1	H334
Eye irritation	Eye Irrit.	2A	H319
Skin sensitization	Skin Sens.	1	H317
Eye irritation	Eye Irrit.	2	H319
Germ cell mutagenicity	Muta.	2	H341

Discovory and Applicatios

Clomiphene citrate, also known as clomiphene, is a well-known drug used primarily to treat female infertility. It belongs to a class of drugs called selective estrogen receptor modulators (SERMs) and has the molecular formula C26H28ClNO·C6H8O7. Clomiphene citrate has a fascinating history and has a wide range of applications in reproductive medicine and beyond.

The discovery of clomiphene citrate dates back to the 1950s. Researchers were exploring ways to induce ovulation in women who were anovulatory or oligoovulatory, meaning they either did not ovulate or ovulated infrequently. Early studies found that certain compounds could affect estrogen receptors in the hypothalamus and pituitary gland, thereby promoting the release of gonadotropins and subsequently inducing ovulation. This study found that clomiphene citrate is a potent ovulation-inducing treatment.

Clomiphene citrate works by binding to estrogen receptors in the hypothalamus, thereby inhibiting the negative feedback mechanism of estrogen. This suppression results in increased secretion of gonadotropin-releasing hormone (GnRH), which in turn leads to elevated follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Increased levels of these hormones stimulate the growth and maturation of ovarian follicles, ultimately leading to ovulation.

The primary application of clomiphene citrate is in the treatment of female infertility, particularly in women with polycystic ovary syndrome (PCOS) or other ovulatory disorders. It is often the treatment of choice due to its efficacy, ease of use, and relatively low cost. Typically, clomiphene citrate is taken orally for five days early in the menstrual cycle. Ovulation typically occurs five to 10 days after the last dose, so intercourse or intrauterine insemination can be timed to increase the chances of conception.

The uses of clomiphene citrate are not limited to inducing ovulation. In men, it has been used to treat male infertility caused by low testosterone levels or insufficient gonadotropin secretion. By stimulating the hypothalamic-pituitary-gonadal axis, clomiphene can increase endogenous testosterone production, thereby improving sperm production and fertility outcomes.

In addition, clomiphene citrate is used in clinical research and treatment protocols for a variety of reproductive health conditions. It has been studied in combination with other drugs and assisted reproductive technologies (ART) to enhance fertility treatments. For example, it is sometimes used with gonadotropins or as part of a controlled ovarian hyperstimulation protocol in an in vitro fertilization (IVF) cycle.

Although clomiphene citrate is generally well tolerated, it is not without side effects. Common side effects include hot flashes, bloating, breast tenderness, and mood swings. More serious but less common side effects include ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy, the latter caused by the induction of multiple follicles.

In recent years, studies have explored the potential of clomiphene citrate for other medical applications. For example, it has been studied in the treatment of gynecomastia in men and certain types of breast cancer in women. Its mechanism of regulating estrogen receptors makes it a candidate for a variety of endocrine-related diseases.

References

Greenblatt, R.B., et al., 1961. "Induction of Ovulation with MRL/41." Fertility and Sterility, Volume 12, Issue 2, pp. 165-177.
Homburg, R., 2005. "Clomiphene Citrate—End of an Era? A Mini-Review." Human Reproduction, Volume 20, Issue 8, pp. 2043-2051.
Practice Committee of the American Society for Reproductive Medicine, 2013. "Use of Clomiphene Citrate in Infertile Women: A Committee Opinion." Fertility and Sterility, Volume 100, Issue 2, pp. 341-348.