Clomifene

Last updated

Clomifene
Clomifene.svg
Clomifene-based-on-xtal-3D-bs-17.png
Clinical data
Trade names Clomid, Serophene, others [1]
Other namesClomiphene; Chloramifene; Chloramiphene; MRL-41; MRL/41; NSC-35770
AHFS/Drugs.com Monograph
Pregnancy
category
  • AU:B3
Routes of
administration 		By mouth
Drug class Selective estrogen receptor modulator; Progonadotropin
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
Pharmacokinetic data
Bioavailability High (>90%)
Metabolism Liver CYP2D6 (with enterohepatic circulation) [2]
Metabolites 4-Hydroxyclomiphene (4-OH-CLO), 4-Hydroxy-N-desethylclomiphene (4-OH-DE-CLO)
Elimination half-life 4 – 7 days [2] [3] [4]

active metabolites:
4-OH-CLO : 13 - 34 hrs [2]

4-OH-DE-CLO : 15 - 37 hrs [2]
Excretion Mainly feces, some in urine
Identifiers
  • (E,Z)-2-(4-(2-chloro-1,2-diphenylethenyl)phenoxy)-N,N-diethylethanamine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.011.826 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C26H28ClNO
Molar mass 405.97 g·mol−1
3D model (JSmol)
  • ClC(c1ccccc1)=C(c2ccc(OCCN(CC)CC)cc2)c3ccccc3
  • 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 Yes check.svgY
  • Key:GKIRPKYJQBWNGO-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Clomifene, also known as clomiphene, is a medication used to treat infertility in women who do not ovulate, including those with polycystic ovary syndrome. [5] It is taken by mouth. [5]

Contents

Common side effects include pelvic pain and hot flashes. [5] Other side effects can include changes in vision, vomiting, trouble sleeping, ovarian cancer, and seizures. [5] [6] It is not recommended in people with liver disease or abnormal vaginal bleeding of unknown cause or who are pregnant. [6] [7] Clomifene is in the selective estrogen receptor modulator (SERM) family of medication and is a nonsteroidal medication. [7] [8] It works by causing the release of GnRH by the hypothalamus, and subsequently gonadotropin from the anterior pituitary. [6]

Clomifene was approved for medical use in the United States in 1967. [5] It is on the World Health Organization's List of Essential Medicines, under the category "Ovulation inducers" (Complementary List). [9] Its introduction began the era of assisted reproductive technology. [10]

Clomifene (particularly the purified enclomiphene isomer) has also been found to have a powerful ability to boost or restore testosterone levels in hypogonadal men. [11] It can be used to enhance performance in sports and is banned by the World Anti-Doping Agency.

Medical uses

Reproductive medicine

Clomifene is one of several alternatives for inducing ovulation in those who are infertile due to anovulation or oligoovulation. [12] Evidence is lacking for the use of clomifene in those who are infertile without a known reason. [13] 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. [12] Clomifene has also been used with other assisted reproductive technology to increase success rates of these other modalities. [14]

Clomifene has been effectively used to restore spermatogenesis in trans women looking to have biological children. [15] The effect of feminizing hormone therapy on fertility is not clear, but it is known that it can prevent sperm production. [16]

Testosterone replacement therapy

Clomifene is sometimes used in the treatment of male hypogonadism as an alternative to testosterone replacement therapy. [17] [ non-primary source needed ] It has been found to increase testosterone levels by 2- to 2.5-times in hypogonadal men at such dosages. [17] [18] Despite the use of questionnaires in testosterone replacement comparator trials being called into question, clomifene's lower cost, therapeutic benefits, and greater value towards hypogonadism improvement have been noted. [19] [ non-primary source needed ]

Clomifene consists of two stereoisomers in equal proportion: enclomifene and zuclomifene. Zuclomifene has pro-estrogenic properties, whereas enclomifene is pro-androgenic, i.e. it promotes testosterone production through stimulation of the HPG axis. For this reason, purified enclomifene isomer has been found to be twice as effective in boosting testosterone compared to the standard mix of both isomers. [11] Additionally, enclomifene has a half-life of just 10 hours, [4] but zuclomifene has a half-life on the order of several days to a week, so if the goal is to boost testosterone, taking regular clomifene may produce far longer-lasting pro-estrogenic effects than pro-androgenic effects. [20]

Gynecomastia

Clomifene has been used in the treatment of gynecomastia. [21] It has been found to be useful in the treatment of some cases of gynecomastia but it is not as effective as tamoxifen or raloxifene for this indication. [22] It has shown variable results for gynecomastia (probably because the zuclomifene isomer is estrogenic), and hence is not recommended for treatment of the condition. [23] Pure enclomifene isomer is likely to be more effective than clomifene at treating gynecomastia, because of the lack of the zuclomifene isomer (as noted above).[ medical citation needed ]

Due to its long half-life, zuclomifene can be detected in urine for at least 261 days after discontinuation [24] (261 days after discontinuation with a half-life of 30 days, there is still 0.24% of the peak level of zuclomifene being excreted, whereas with a half-life of 10 hours, enclomifene reaches the same 0.24% level in less than 4 days[ medical citation needed ]).

Prohibited use in sports

The World Anti-Doping Agency (WADA) prohibits clomifene under category S4 of hormone and metabolic modulators. It can be present as an undeclared ingredient in black market products available online to enhance athletic performance. Like other substances with anabolic properties, clomifene leads to increased muscle mass in males. [25]

Because clomifene can enhance egg production in hens, athletes may inadvertently consume the substance through contaminated food. A WADA study found that clomifene given to laying hens migrates into their eggs but was able to develop a method of distinguishing egg ingestion from doping. [26]

Contraindications

Contraindications include an allergy to the medication, pregnancy, prior liver problems, abnormal vaginal bleeding of unclear cause, ovarian cysts other than those due to polycystic ovarian syndrome, unmanaged adrenal or thyroid problems, and pituitary tumors. [7]

Side effects

The most common adverse drug reaction associated with the use of clomifene (>10% of people) is reversible ovarian enlargement. [7]

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), light sensitivity and pupil constriction, abnormal uterine bleeding and/or abdominal discomfort. [7]

Rare adverse events (<1% of people) include: high blood level of triglycerides, liver inflammation, reversible baldness and/or ovarian hyperstimulation syndrome. [7]

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

Rates of birth defects and miscarriages do not appear to change with the use of clomifene for fertility. [7] Clomifene has been associated with liver abnormalities and a couple of cases of hepatotoxicity. [27]

Cancer risk

Some studies have suggested that clomifene if used for more than a year may increase the risk of ovarian cancer. [13] This may only be the case in those who have never been and do not become pregnant. [28] Subsequent studies have failed to support those findings. [12] [29]

Clomifene has been shown to be associated with an increased risk of malignant melanomas and thyroid cancer. [3] Thyroid cancer risk was not associated with the number of pregnancies carried to viability. [30]

Pharmacology

Pharmacodynamics

Selective estrogen receptor modulator activity

Clomifene is a nonsteroidal triphenylethylene derivative that acts as a selective estrogen receptor modulator (SERM). [14] It consists of a non-racemic mixture of zuclomifene (~38%) and enclomifene (~62%), each of which has unique pharmacologic properties. [31] It is a mixed agonist and antagonist of the estrogen receptor (ER). Clomifene activates the ERα in the setting of low baseline estrogen levels and partially blocks the receptor in the context of high baseline estrogen levels. [18] Conversely, it is an antagonist of the ERβ. [18] Clomifene has antiestrogenic effects in the uterus. [32] There is little clinical research on the influence of clomifene in many target tissues, such as lipids, the cardiovascular system, and the breasts. [32] [33] Positive effects of clomifene on bone have been observed. [18] [32] [33] Clomifene has been found to decrease insulin-like growth factor 1 (IGF-1) levels in women. [34]

Clomifene is a long-acting ER ligand, with a nuclear retention of greater than 48 hours. [35] Clomifene is a prodrug being activated via similar metabolic pathways as the related triphenylethylene SERMs tamoxifen and toremifene. [36] [37] The affinity of clomifene for the ER relative to estradiol ranges from 0.1 to 12% in different studies, which is similar to the range for tamoxifen (0.06–16%). [38] [39] [40] 4-Hydroxyclomifene, a major active metabolite of clomifene, and afimoxifene (4-hydroxytamoxifen), a major active metabolite of tamoxifen, show 89–251% and 41–246% of the affinity of estradiol for the ER in human MCF-7 breast cancer cells, respectively. [41] [42] The ER affinities of the isomers of 4-hydroxyclomifene were 285% for (E)-4-hydroxyclomifene and 16% for (Z)-4-hydroxyclomifene relative to estradiol. [41] 4-Hydroxy-N-desmethylclomifene has similar affinity to 4-hydroxyclomifene for the ER. [37] In one study, the affinities of clomifene and its metabolites for the ERα were ~100 nM for clomifene, ~2.4 nM for 4-hydroxyclomifene, ~125 nM for N-desmethylclomifene, and ~1.4 nM for 4-hydroxy-N-desmethylclomifene. [37]

Even though clomifene has some estrogenic effect, the antiestrogenic property is believed to be the primary source for stimulating ovulation. [5] Clomifene appears to act mostly in the hypothalamus where it depletes hypothalamic ERs and blocks the negative feedback effect of circulating endogenous estradiol, which in turn results in an increase in hypothalamic gonadotropin-releasing hormone (GnRH) pulse frequency and circulating concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH).[ medical citation needed ]

In normal physiologic female hormonal cycling, at seven 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.[ medical citation needed ] If fertilization does not occur in the post-ovulation period the corpus luteum disintegrates due to a lack of human chorionic gonadotropin (hCG).[ medical citation needed ] This would normally be produced by the embryo in the effort of maintaining progesterone and estrogen levels during pregnancy.[ medical citation needed ]

Therapeutically, clomifene is given early in the menstrual cycle to produce follicles.[ medical citation needed ] Follicles, in turn, produce the estrogen, which circulates in serum.[ medical citation needed ] In the presence of clomifene, the body perceives a low level of estrogen, similar to day 22 in the previous cycle.[ medical citation needed ] Since estrogen can no longer effectively exert negative feedback on the hypothalamus, GnRH secretion becomes more rapidly pulsatile, which results in increased pituitary gonadotropin release.[ medical citation needed ] (More rapid, lower amplitude pulses of GnRH lead to increased LH and FSH secretion, while more irregular, larger amplitude pulses of GnRH leads to a decrease in the ratio of LH to FSH.[ medical citation needed ]) Increased FSH levels cause the growth of more ovarian follicles, and subsequently rupture of follicles resulting in ovulation. Ovulation occurs most often 6 to 7 days after a course of clomifene.[ medical citation needed ]

In normal men, 50 mg/day clomifene for 8 months has been found to increase testosterone levels by around 870 ng/dL in younger men and by around 490 ng/dL in elderly men. [18] Estradiol levels increased by 62 pg/mL in younger men and by 40 pg/mL in elderly men. [18] These findings suggest that the progonadotropic effects of clomifene are stronger in younger men than in older men. [18] In men with hypogonadism, clomifene has been found to increase testosterone levels by 293 to 362 ng/dL and estradiol levels by 5.5 to 13 pg/mL. [18] In a large clinical study of men with low testosterone levels (<400 ng/dL), 25 mg/day clomifene increased testosterone levels from 309 ng/dL to 642 ng/dL after 3 months of therapy. [43] No significant changes in HDL cholesterol, triglycerides, fasting glucose, or prolactin levels were observed, although total cholesterol levels decreased significantly. [18] [43]

Tissue-specific estrogenic and antiestrogenic activity of SERMs
Medication Breast Bone Liver Uterus Vagina Brain
Lipids Coagulation SHBG Tooltip Sex hormone-binding globulin IGF-1 Tooltip Insulin-like growth factor 1 Hot flashes Gonadotropins
Estradiol ++++++++++
"Ideal SERM"–++±±±–++±
Bazedoxifene –++++ ?–±– ?
Clomifene–++ ?++– ?–±
Lasofoxifene –+++ ? ?±±– ?
Ospemifene –+++++±±–±
Raloxifene –+++++±––±
Tamoxifen –++++++––±
Toremifene –++++++––±
Effect:+ = Estrogenic / agonistic. ± = Mixed or neutral. – = Antiestrogenic / antagonistic. Note: SERMs generally increase gonadotropin levels in hypogonadal and eugonadal men as well as premenopausal women (antiestrogenic) but decrease gonadotropin levels in postmenopausal women (estrogenic). Sources: See template.

Other activities

Clomifene is an inhibitor of the conversion of desmosterol into cholesterol by the enzyme 24-dehydrocholesterol reductase. [44] [45] Concerns about possible induction of desmosterolosis and associated symptoms such as cataracts and ichthyosis with extended exposure precluded the use of clomifene in the treatment of breast cancer. [44] [45] Continuous use of clomifene has been found to increase desmosterol levels by 10% and continuous high doses of clomifene (200 mg/day) have been reported to produce visual disturbances. [46] [47]

Pharmacokinetics

Clomifene produces N-desmethylclomifene, clomifenoxide (clomifene N-oxide), 4-hydroxyclomifene, and 4-hydroxy-N-desmethylclomifene as metabolites. [2] [48] Clomifene is a prodrug most importantly of 4-hydroxyclomifene and 4-hydroxy-N-desmethylclomifene, which are the most active of its metabolites. [36] [37] In one study, the peak levels after a single 50 mg dose of clomifene were 20.37 nmol/L for clomifene, 0.95 nmol/L for 4-hydroxyclomifene, and 1.15 nmol/L for 4-hydroxy-N-desmethylclomifene. [2]

Clomifene has an onset of action of 5 to 10 days following course of treatment and an elimination half-life about 4 - 7days. [2] [4] In one study, after a single 50 mg dose of clomifene, the half-life of clomifene was 128 hours (5.3 days), of 4-hydroxyclomifene was 13 hours, and of 4-hydroxy-N-desmethylclomifene was 15 hours. [2] Individuals with the CYP2D6*10 allele showed longer half-lives for 4-hydroxyclomifene and 4-hydroxy-N-desmethylclomifene. [2] Primarily due to differences in CYP2D6 genetics, steady state concentrations and individual response to clomifene are highly variable. [49]

Most clomifene metabolism occurs in the liver, where it undergoes enterohepatic recirculation. Clomifene and its metabolites are excreted primarily through feces (42%), and excretion can occur up to 6 weeks after discontinuation. [31]

Chemistry

Clomifene is a triphenylethylene derivative. It is a mixture of two geometric isomers, the cis enclomifene ((E)-clomifene) form and trans zuclomifene ((Z)-clomifene) form. These two isomers contribute to the mixed estrogenic and antiestrogenic properties of clomifene. [10] The typical ratio of these isomers after synthesis is 38% zuclomiphene and 62% enclomiphene. [4] The United States Pharmacopeia specifies that clomifene preparations must contain between 30% and 50% zuclomiphene. [4]

Enclomifene Enclomifene.png
Enclomifene
Zuclomifene Zuclomifene.png
Zuclomifene

History

A team at William S. Merrell Chemical Company led by Frank Palopoli synthesized clomifene in 1956; after its biological activity was confirmed a patent was filed and issued in November 1959. [10] [50] Scientists at Merrell had previously synthesized chlorotrianisene and ethamoxytriphetol. [10] Clomifene was studied in the treatment of advanced breast cancer during the period of 1964 to 1974 and was found to be effective but was abandoned due to concerns about desmosterolosis with extended use. [44] [51] [52] Short-term use (e.g. days to months) did not raise the same concerns and clomifene continued to be studied for other indications. [45] [46]

Comparison of early clinical experience with antiestrogens for advanced breast cancer
AntiestrogenDosageYear(s)Response rateAdverse effects
Ethamoxytriphetol 500–4,500 mg/day196025% Acute psychotic episodes
Clomifene100–300 mg/day1964–197434%Risks of cataracts
Nafoxidine 180–240 mg/day197631% Cataracts, ichthyosis, photophobia
Tamoxifen 20–40 mg/day1971–197331%Transient thrombocytopenia a
Footnotes:a = "The particular advantage of this drug is the low incidence of troublesome side effects (25)." "Side effects were usually trivial (26)." Sources: [51] [53]

Clinical studies were conducted under an Investigational New Drug Application; clomifene was third drug for which an IND had been filed under the 1962 Kefauver Harris Amendment to the Federal Food, Drug, and Cosmetic Act that had been passed in response to the thalidomide tragedy. [10] It was approved for marketing in 1967 under the brand name Clomid. [10] [54] 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. [55]

The drug is widely considered to have been a revolution in the treatment of female infertility, the beginning of the modern era of assisted reproductive technology, and the beginning of what in the words of Eli Y. Adashi, was "the onset of the US multiple births epidemic". [10] [56]

The company was acquired by Dow Chemical in 1980, [57] [58] and in 1989 Dow Chemical acquired 67 percent interest of Marion Laboratories, which was renamed Marion Merrell Dow. [57] In 1995 Hoechst AG acquired the pharmaceutical business of Marion Merrell Dow. [59] Hoechst in turn became part of Aventis in 1999, [60] : 9–11  and subsequently a part of Sanofi. [61] It became the most widely prescribed drug for ovulation induction to reverse anovulation or oligoovulation. [62]

Society and culture

Brand names

Clomifene is marketed under many brand names worldwide, including Beclom, Bemot, Biogen, Blesifen, Chloramiphene, Clofert, Clomene, ClomHEXAL, Clomi, Clomid, Clomidac, Clomifen, Clomifencitrat, Clomifene, Clomifène, Clomifene citrate, Clomifeni citras, Clomifeno, Clomifert, Clomihexal, Clomiphen, Clomiphene, Clomiphene Citrate, Cloninn, Clostil, Clostilbegyt, Clovertil, Clovul, Dipthen, Dufine, Duinum, Fensipros, Fertab, Fertec, Fertex, Ferticlo, Fertil, Fertilan, Fertilphen, Fertin, Fertomid, Ferton, Fertotab, Fertyl, Fetrop, Folistim, Genoclom, Genozym, Hete, I-Clom, Ikaclomin, Klofit, Klomen, Klomifen, Lomifen, MER 41, Milophene, Ofertil, Omifin, Ova-mit, Ovamit, Ovinum, Ovipreg, Ovofar, Ovuclon, Ovulet, Pergotime, Pinfetil, Profertil, Prolifen, Provula, Reomen, Serofene, Serophene, Serpafar, Serpafar, Surole, Tocofeno, and Zimaquin. [1]

Regulation

Clomifene is included on the World Anti-Doping Agency list of illegal doping agents in sport. [63] It is listed because it is an "anti-estrogenic substance".[ citation needed ]

Research

Clomifene has been used almost exclusively for ovulation induction in premenopausal women, and has been studied very limitedly in postmenopausal women. [64]

Clomifene was studied for treatment and prevention of breast cancer, but issues with toxicity led to abandonment of this indication, as did the discovery of tamoxifen. [65] Like the structurally related drug triparanol, clomifene is known to inhibit the enzyme 24-dehydrocholesterol reductase and increase circulating desmosterol levels, making it unfavorable for extended use in breast cancer due to risk of side effects like irreversible cataracts. [66] [67]

Related Research Articles

Anovulation is when the ovaries do not release an oocyte during a menstrual cycle. Therefore, ovulation does not take place. However, a woman who does not ovulate at each menstrual cycle is not necessarily going through menopause. Chronic anovulation is a common cause of infertility.

Hypogonadism means diminished functional activity of the gonads—the testicles or the ovaries—that may result in diminished production of sex hormones. Low androgen levels are referred to as hypoandrogenism and low estrogen as hypoestrogenism. These are responsible for the observed signs and symptoms in both males and females.

<span class="mw-page-title-main">Selective estrogen receptor modulator</span> Drugs acting on the estrogen receptor

Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonists/antagonists (ERAAs), are a class of drugs that act on estrogen receptors (ERs). Compared to pure ER agonists–antagonists, SERMs are more tissue-specific, allowing them to selectively inhibit or stimulate estrogen-like action in various tissues.

<span class="mw-page-title-main">Tamoxifen</span> Medication

Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and men. It is also being studied for other types of cancer. It has been used for Albright syndrome. Tamoxifen is typically taken daily by mouth for five years for breast cancer.

Fertility medications, also known as fertility drugs, are medications which enhance reproductive fertility. For women, fertility medication is used to stimulate follicle development of the ovary. There are very few fertility medication options available for men.

<span class="mw-page-title-main">Aromatase inhibitor</span> Class of drugs

Aromatase inhibitors (AIs) are a class of drugs used in the treatment of breast cancer in postmenopausal women and in men, and gynecomastia in men. They may also be used off-label to reduce estrogen conversion when supplementing testosterone exogenously. They may also be used for chemoprevention in women at high risk for breast cancer.

<span class="mw-page-title-main">Hypothalamic–pituitary–gonadal axis</span> Concept of regarding the hypothalamus, pituitary gland and gonadal glands as a single entity

The hypothalamic–pituitary–gonadal axis refers to the hypothalamus, pituitary gland, and gonadal glands as if these individual endocrine glands were a single entity. Because these glands often act in concert, physiologists and endocrinologists find it convenient and descriptive to speak of them as a single system.

<span class="mw-page-title-main">Letrozole</span> Breast cancer drug

Letrozole, sold under the brand name Femara among others, is an aromatase inhibitor medication that is used in the treatment of breast cancer.

Ovulation induction is the stimulation of ovulation by medication. It is usually used in the sense of stimulation of the development of ovarian follicles to reverse anovulation or oligoovulation.

<span class="mw-page-title-main">Chlorotrianisene</span> Chemical compound

Chlorotrianisene (CTA), also known as tri-p-anisylchloroethylene (TACE) and sold under the brand name Tace among others, is a nonsteroidal estrogen related to diethylstilbestrol (DES) which was previously used in the treatment of menopausal symptoms and estrogen deficiency in women and prostate cancer in men, among other indications, but has since been discontinued and is now no longer available. It is taken by mouth.

<span class="mw-page-title-main">Enclomifene</span> Chemical compound

Enclomifene (INNTooltip International Nonproprietary Name), or enclomiphene (USANTooltip United States Adopted Name), a nonsteroidal selective estrogen receptor modulator of the triphenylethylene group, acts by antagonizing the estrogen receptor (ER) in the pituitary gland, which reduces negative feedback by estrogen on the hypothalamic-pituitary-gonadal axis, thereby increasing gonadotropin secretion and hence gonadal production of testosterone. It is one of the two stereoisomers of clomifene, which itself is a mixture of 38% zuclomifene and 62% enclomifene. Enclomifene is the (E)-stereoisomer of clomifene, while zuclomifene is the (Z)-stereoisomer. Whereas zuclomifene is more estrogenic, enclomifene is more antiestrogenic. In accordance, unlike enclomifene, zuclomifene is antigonadotropic due to activation of the ER and reduces testosterone levels in men. As such, isomerically pure enclomifene is more favorable than clomifene as a progonadotropin for the treatment of male hypogonadism.

<span class="mw-page-title-main">Selective androgen receptor modulator</span> Class of pharmaceutical drugs

Selective androgen receptor modulators (SARMs) are a class of drugs that selectively activate the androgen receptor in specific tissues, promoting muscle and bone growth while having less effect on male reproductive tissues like the prostate gland.

Antiestrogens, also known as estrogen antagonists or estrogen blockers, are a class of drugs which prevent estrogens like estradiol from mediating their biological effects in the body. They act by blocking the estrogen receptor (ER) and/or inhibiting or suppressing estrogen production. Antiestrogens are one of three types of sex hormone antagonists, the others being antiandrogens and antiprogestogens. Antiestrogens are commonly used to stop steroid hormones, estrogen, from binding to the estrogen receptors leading to the decrease of estrogen levels. Decreased levels of estrogen can lead to complications in sexual development.

<span class="mw-page-title-main">Nafoxidine</span> Chemical compound

Nafoxidine or nafoxidine hydrochloride is a nonsteroidal selective estrogen receptor modulator (SERM) or partial antiestrogen of the triphenylethylene group that was developed for the treatment of advanced breast cancer by Upjohn in the 1970s but was never marketed. It was developed at around the same time as tamoxifen and clomifene, which are also triphenylethylene derivatives. The drug was originally synthesized by the fertility control program at Upjohn as a postcoital contraceptive, but was subsequently repurposed for the treatment of breast cancer. Nafoxidine was assessed in clinical trials in the treatment of breast cancer and was found to be effective. However, it produced side effects including ichthyosis, partial hair loss, and phototoxicity of the skin in almost all patients, and this resulted in the discontinuation of its development.

<span class="mw-page-title-main">Gynecomastia</span> Endocrine system disorder of human male breast

Gynecomastia is the abnormal non-cancerous enlargement of one or both breasts in males due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. Gynecomastia can cause significant psychological distress or unease.

<span class="mw-page-title-main">Ethamoxytriphetol</span> Chemical compound

Ethamoxytriphetol is a synthetic nonsteroidal antiestrogen that was studied clinically in the late 1950s and early 1960s but was never marketed. MER-25 was first reported in 1958, and was the first antiestrogen to be discovered. It has been described as "essentially devoid of estrogenic activity" and as having "very low estrogenic activity in all species tested". However, some estrogenic effects in the uterus have been observed, so it is not a pure antiestrogen but is, instead, technically a selective estrogen receptor modulator (SERM). For all intents and purposes, it is a nearly pure antiestrogen, however.

<span class="mw-page-title-main">Etacstil</span> Chemical compound

Etacstil is an orally active, nonsteroidal, combined selective estrogen receptor modulator (SERM) and selective estrogen receptor degrader (SERD) that was developed for the treatment of estrogen receptor-positive breast cancer. It was shown to overcome antiestrogen resistance in breast cancer by altering the shape of the estrogen receptor, thus exhibiting SERD properties. Etacstil is a tamoxifen derivative and one of the first drugs to overcome tamoxifen-resistance. It is the predecessor of GW-7604, of which etacstil is a prodrug. This is analogous to the case of tamoxifen being a prodrug of afimoxifene (4-hydroxytamoxifen).

<span class="mw-page-title-main">Triphenylchloroethylene</span> Synthetic form of estrogen

Triphenylchloroethylene, or triphenylchlorethylene, also known as chlorotriphenylethylene or as phenylstilbene chloride, is a synthetic nonsteroidal estrogen of the triphenylethylene group that was marketed in the 1940s for the treatment of menopausal symptoms, vaginal atrophy, lactation suppression, and all other estrogen-indicated conditions.

<span class="mw-page-title-main">Nitromifene</span> Chemical compound

Nitromifene (INNTooltip International Nonproprietary Name; also as the citrate salt nitromifene citrate (USANTooltip United States Adopted Name), developmental code names CI-628, CN-5518, CN-55945) is a nonsteroidal selective estrogen receptor modulator (SERM) related to triphenylethylenes like tamoxifen that was never marketed. It is a mixture of (E)- and (Z)-isomers that possess similar antiestrogenic activity. The drug was described in 1966. Along with tamoxifen, nafoxidine, and clomifene, it was one of the earliest SERMs.

References

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