Enclomifene

Last updated
Enclomifene
Enclomifene.png
Clinical data
Trade names Androxal
Other namesEnclomiphene; (E)-Clomifene; RMI-16289; Enclomid; Enclomifene citrate; Enclomiphene citrate
Routes of
administration 		By mouth
Drug class Selective estrogen receptor modulator; Progonadotropin
Pharmacokinetic data
Metabolism liver, CYP2D6 and CYP3A4 [1]
Elimination half-life 10 hours [2]
Identifiers
  • 2-[4-[(E)-2-chloro-1,2-diphenylethenyl]phenoxy]-N,N-diethylethanamine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C26H28ClNO
Molar mass 405.97 g·mol−1
3D model (JSmol)
  • CCN(CC)CCOC1=CC=C(C=C1)/C(=C(\C2=CC=CC=C2)/Cl)/C3=CC=CC=C3
  • 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/b26-25+
  • Key:GKIRPKYJQBWNGO-OCEACIFDSA-N

Enclomifene (INN Tooltip International Nonproprietary Name), or enclomiphene (USAN Tooltip 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. [3] It is one of the two stereoisomers of clomifene, which itself is a mixture of 38% zuclomifene and 62% enclomifene. [3] Enclomifene is the (E)-stereoisomer of clomifene, while zuclomifene is the (Z)-stereoisomer. [4] [5] Whereas zuclomifene is more estrogenic, enclomifene is more antiestrogenic. [3] In accordance, unlike enclomifene, zuclomifene is antigonadotropic due to activation of the ER and reduces testosterone levels in men. [3] As such, isomerically pure enclomifene is more favorable than clomifene as a progonadotropin for the treatment of male hypogonadism. [3]

Contents

Enclomiphene (former tentative brand names Androxal and EnCyzix), was under development for the treatment of male hypogonadism and type 2 diabetes. [4] [5] [6] [3] By December 2016, it was in preregistration and was under review by the Food and Drug Administration in the United States and the European Medicines Agency in the European Union. [6] In January 2018, the Committee for Medicinal Products for Human Use of the European Medicines Agency recommended refusal of marketing authorization for enclomifene for the treatment of secondary hypogonadism. [7] In April 2021, development of enclomifene was discontinued for all indications. [6]

Medical uses

Enclomiphene is primarily used as a treatment for men with persistent low testosterone as a result of secondary hypogonadotropic hypogonadism. In secondary hypogonadotropic hypogonadism, the resulting low levels of testosterone is attributed to inadequacies in the hypothalamic-pituitary-gonadal axis. In contrast, primary hypogonadism is caused by defects in the testes that causes them to be unable to produce the required amount of testosterone.

Enclomiphene, which stimulates the endogenous production of testosterone, is not currently known to have common adverse effects of exogenous testosterone replacement therapy, such as reduced spermatogenesis or infertility. [8] [9]

Contraindications

Enclomiphene citrate is contraindicated in the groups of individuals below:

Adverse effects

The adverse effects of enclomiphene has not been extensively studied. [10] Enclomiphene is a selective estrogen receptor modulator (SERM), which is associated with an increased risk of thrombo-embolic events. [11] Enclomiphene, unlike testosterone replacement therapy, is not associated with infertility or decreased spermatogenesis. [11]

The following adverse events were observed in a population of 1,403 persons participating in phase 2 and phase 3 studies of enclomiphene: [11]

Adverse EventFrequency % (N)
Headache1.6% (23)
Hot flush1.1% (16)
Nausea1.0% (14)
Muscle spasms0.9% (12)
Dizziness0.7% (10)
Fatigue0.6% (9)
Hematocrit increased0.6% (9)
Erectile dysfunction0.6% (8)
PSA increased0.6% (8)
Increased appetite0.6% (8)
Vision blurred0.5% (7)
Aggression0.5% (7)
Irritability0.5% (7)
Acne0.5% (7)
Deep vein thrombosis 0.2% (3)
Pulmonary embolism 0.1% (1)
Ischemic stroke (fatal)0.1% (1)

Mechanism of action

Enclomiphene is a selective estrogen receptor antagonist, antagonizing the estrogen receptors in the pituitary gland, disrupting the negative feedback loop by estrogen towards the hypothalamic-pituitary-gonadal axis, ultimately resulting in an increase in gonadotropin secretion.

In men with secondary hypogonadotropic hypogonadism, this improves testosterone levels and sperm motility. Men with secondary hypogonadotropic hypogonadism have abnormally low testosterone levels due to low-normal levels of luteinizing hormone (LH) and follicular stimulating hormone (FSH). The biological role of these hormones is to stimulate the endogenous production of testosterone by the testes.

Common symptoms of secondary hypogonadotropic hypogonadism include low libido, energy, and mood. In addition, men with low testosterone may experience osteoporosis, an increase in visceral fat, and the regression of secondary sexual characteristics. [12] Enclomiphene stimulates the endogenous production of testosterone. It works differently from traditional testosterone replacement therapy, which replaces testosterone using an exogenous source.

In addition, research has uncovered that enclomiphene increases total and free testosterone levels without increasing dihydrotestosterone disproportionately, suggesting that it "normalizes endogenous testosterone production pathways and restores normal testosterone levels in men with secondary hypogonadism." [13]

History

Enclomifene or Enclomiphene (former tentative brand names Androxal and EnCyzix), was under development for the treatment of male hypogonadism and type 2 diabetes. [4] [5] [6] [3] By December 2016, it was in preregistration and was under review by the Food and Drug Administration in the United States and the European Medicines Agency in the European Union. [6] In January 2018, the Committee for Medicinal Products for Human Use of the European Medicines Agency recommended refusal of marketing authorization for enclomifene for the treatment of secondary hypogonadism. [7] In April 2021, development of enclomifene was discontinued for all indications. [6]

Clomiphene citrate, which enclomiphene citrate is derived from, is a drug approved by the Food and Drug Association (FDA) for indications of anovulatory or oligo-ovulatory infertility and male infertility (spermatogenesis induction). [14]

A media release by the FDA for the pharmacy compounding advisory committee compared the efficacy of testosterone replacement therapy against enclomiphene. They wrote that while testosterone replacement therapy often resulted in side effects such as transference risk, supranormal testosterone levels, suppressed spermatogenesis, suppressed testicular function, and testicular atrophy, none of these risks are present in enclomiphene. [15]

In 2009, a study discovered that "short-term clinical safety data for enclomiphene have been satisfactory and equivalent to safety data for testosterone gels and placebo." [16]

In 2016, a study on enclomiphene citrate reported that "the ability [of enclomiphene citrate] to treat testosterone deficiency in men while maintaining fertility supports a role for enclomiphene citrate in the treatment of men in whom testosterone therapy is not a suitable option." [17]

In 2019, a study was published that found that "enclomiphene has been shown to increase testosterone levels while stimulating [follicular-stimulating hormone] and [luteinizing hormone] production." [18]

The key difference between enclomiphene citrate and traditional testosterone replacement therapy is that enclomiphene citrate stimulates the body to produce its own testosterone, while traditional testosterone replacement therapy replaces low testosterone levels in men with exogenous, synthetic testosterone.

A study conducted in 2013 offered this assessment of the potential of enclomiphene citrate to increase sexual function in men: "If enclomiphene citrate can correct the central defect in men that blocks their ability to produce [lutenizing hormone] and [follicular-stimulating hormone] and thus to produce both testosterone and sperm in the testes, this drug may prove itself superior to other treatments." [12]

Related Research Articles

<span class="mw-page-title-main">Androgen</span> Any steroid hormone that promotes male characteristics

An androgen is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes the embryological development of the primary male sex organs, and the development of male secondary sex characteristics at puberty. Androgens are synthesized in the testes, the ovaries, and the adrenal glands.

Hormone therapy or hormonal therapy is the use of hormones in medical treatment. Treatment with hormone antagonists may also be referred to as hormonal therapy or antihormone therapy. The most general classes of hormone therapy are oncologic hormone therapy, hormone replacement therapy, androgen replacement therapy (ART), oral contraceptive pills, and transgender hormone therapy.

<span class="mw-page-title-main">Luteinizing hormone</span> Gonadotropin secreted by the adenohypophysis

Luteinizing hormone is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (GnRH) from the hypothalamus. In females, an acute rise of LH known as an LH surge, triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell–stimulating hormone (ICSH), it stimulates Leydig cell production of testosterone. It acts synergistically with follicle-stimulating hormone (FSH).

Delayed puberty is when a person lacks or has incomplete development of specific sexual characteristics past the usual age of onset of puberty. The person may have no physical or hormonal signs that puberty has begun. In the United States, girls are considered to have delayed puberty if they lack breast development by age 13 or have not started menstruating by age 15. Boys are considered to have delayed puberty if they lack enlargement of the testicles by age 14. Delayed puberty affects about 2% of adolescents.

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">Clomifene</span> Infertility treatment for women

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

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">Buserelin</span> Chemical compound

Buserelin, sold under the brand name Suprefact among others, is a medication which is used primarily in the treatment of prostate cancer and endometriosis. It is also used for other indications such as the treatment of premenopausal breast cancer, uterine fibroids, and early puberty, in assisted reproduction for female infertility, and as a part of transgender hormone therapy. In addition, buserelin is used in veterinary medicine. The medication is typically used as a nasal spray three times per day, but is also available for use as a solution or implant for injection into fat.

<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">Gonadotropin-releasing hormone agonist</span> Drug class affecting sex hormones

A gonadotropin-releasing hormone agonist is a type of medication which affects gonadotropins and sex hormones. They are used for a variety of indications including in fertility medicine and to lower sex hormone levels in the treatment of hormone-sensitive cancers such as prostate cancer and breast cancer, certain gynecological disorders like heavy periods and endometriosis, high testosterone levels in women, early puberty in children, as a part of transgender hormone therapy, and to delay puberty in transgender youth among other uses. It is also used in the suppression of spontaneous ovulation as part of controlled ovarian hyperstimulation, an essential component in IVF. GnRH agonists are given by injections into fat, as implants placed into fat, and as nasal sprays.

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">Trestolone</span> Chemical compound

Trestolone, also known as 7α-methyl-19-nortestosterone (MENT), is an experimental androgen/anabolic steroid (AAS) and progestogen medication which has been under development for potential use as a form of hormonal birth control for men and in androgen replacement therapy for low testosterone levels in men but has never been marketed for medical use. It is given as an implant that is placed into fat. As trestolone acetate, an androgen ester and prodrug of trestolone, the medication can also be given by injection into muscle.

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

Zuclomifene (INN; or zuclomiphene (USAN)) is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group that was never marketed. It is one of the two stereoisomers of clomifene, which itself is a mixture of 38% zuclomifene and 62% enclomifene. Zuclomifene is the (Z)-stereoisomer of clomifene, while enclomifene is the (E)-stereoisomer. Whereas zuclomifene is described as mildly estrogenic, enclomifene is described as antiestrogenic. In accordance, unlike enclomifene, zuclomifene is antigonadotropic due to activation of the estrogen receptor and reduces testosterone levels in men. It is also about five times more potent than enclomifene in inducing ovulation.

Hypergonadotropic hypogonadism (HH), also known as primary or peripheral/gonadal hypogonadism or primary gonadal failure, is a condition which is characterized by hypogonadism which is due to an impaired response of the gonads to the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and in turn a lack of sex steroid production. As compensation and the lack of negative feedback, gonadotropin levels are elevated. Individuals with HH have an intact and functioning hypothalamus and pituitary glands so they are still able to produce FSH and LH. HH may present as either congenital or acquired, but the majority of cases are of the former nature. HH can be treated with hormone replacement therapy.

Gonadotropin-releasing hormone (GnRH) insensitivity also known as Isolated gonadotropin-releasing hormone (GnRH)deficiency (IGD) is a rare autosomal recessive genetic and endocrine syndrome which is characterized by inactivating mutations of the gonadotropin-releasing hormone receptor (GnRHR) and thus an insensitivity of the receptor to gonadotropin-releasing hormone (GnRH), resulting in a partial or complete loss of the ability of the gonads to synthesize the sex hormones. The condition manifests itself as isolated hypogonadotropic hypogonadism (IHH), presenting with symptoms such as delayed, reduced, or absent puberty, low or complete lack of libido, and infertility, and is the predominant cause of IHH when it does not present alongside anosmia.

Hypogonadotropic hypogonadism (HH), is due to problems with either the hypothalamus or pituitary gland affecting the hypothalamic-pituitary-gonadal axis. Hypothalamic disorders result from a deficiency in the release of gonadotropic releasing hormone (GnRH), while pituitary gland disorders are due to a deficiency in the release of gonadotropins from the anterior pituitary. GnRH is the central regulator in reproductive function and sexual development via the HPG axis. GnRH is released by GnRH neurons, which are hypothalamic neuroendocrine cells, into the hypophyseal portal system acting on gonadotrophs in the anterior pituitary. The release of gonadotropins, LH and FSH, act on the gonads for the development and maintenance of proper adult reproductive physiology. LH acts on Leydig cells in the male testes and theca cells in the female. FSH acts on Sertoli cells in the male and follicular cells in the female. Combined this causes the secretion of gonadal sex steroids and the initiation of folliculogenesis and spermatogenesis. The production of sex steroids forms a negative feedback loop acting on both the anterior pituitary and hypothalamus causing a pulsatile secretion of GnRH. GnRH neurons lack sex steroid receptors and mediators such as kisspeptin stimulate GnRH neurons for pulsatile secretion of GnRH.

Follicle-stimulating hormone (FSH) insensitivity, or ovarian insensitivity to FSH in females, also referable to as ovarian follicle hypoplasia or granulosa cell hypoplasia in females, is a rare autosomal recessive genetic and endocrine syndrome affecting both females and males, with the former presenting with much greater severity of symptomatology. It is characterized by a resistance or complete insensitivity to the effects of follicle-stimulating hormone (FSH), a gonadotropin which is normally responsible for the stimulation of estrogen production by the ovaries in females and maintenance of fertility in both sexes. The condition manifests itself as hypergonadotropic hypogonadism, reduced or absent puberty, amenorrhea, and infertility in females, whereas males present merely with varying degrees of infertility and associated symptoms.

Androgen deficiency is a medical condition characterized by insufficient androgenic activity in the body. Androgen deficiency most commonly affects women, and is also called Female androgen insufficiency syndrome (FAIS), although it can happen in both sexes. Androgenic activity is mediated by androgens, and is dependent on various factors including androgen receptor abundance, sensitivity and function. Androgen deficiency is associated with lack of energy and motivation, depression, lack of desire (libido), and in more severe cases changes in secondary sex characteristics.

References

  1. ↑ Ghobadi C, Gregory A, Crewe HK, Rostami-Hodjegan A, Lennard MS (2008). "CYP2D6 is primarily responsible for the metabolism of clomiphene". Drug Metabolism and Pharmacokinetics. 23 (2): 101–105. doi:10.2133/dmpk.23.101. PMID   18445989.
  2. ↑ Mikkelson TJ, Kroboth PD, Cameron WJ, Dittert LW, Chungi V, Manberg PJ (September 1986). "Single-dose pharmacokinetics of clomiphene citrate in normal volunteers". Fertility and Sterility. 46 (3): 392–396. doi:10.1016/s0015-0282(16)49574-9. PMID   3091405.
  3. 1 2 3 4 5 6 7 Hill S, Arutchelvam V, Quinton R (February 2009). "Enclomiphene, an estrogen receptor antagonist for the treatment of testosterone deficiency in men". IDrugs. 12 (2): 109–119. PMID   19204885.
  4. 1 2 3 Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 298–. ISBN   978-1-4757-2085-3.
  5. 1 2 3 Morton IK, Hall JM (31 October 1999). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 79–. ISBN   978-0-7514-0499-9.
  6. 1 2 3 4 5 6 "Enclomifene - Repros Therapeutics". AdisInsight. Springer Nature Switzerland AG.
  7. 1 2 "EnCyzix". 17 September 2018.
  8. ↑ Khodamoradi K, Khosravizadeh Z, Parmar M, Kuchakulla M, Ramasamy R, Arora H (January 2021). "Exogenous testosterone replacement therapy versus raising endogenous testosterone levels: current and future prospects". F&S Reviews. 2 (1): 32–42. doi:10.1016/j.xfnr.2020.11.001. PMC   7894643 . PMID   33615283.
  9. ↑ Yazdani N, Matthews Branch S (March 2018). "Daily subcutaneous testosterone for management of testosterone deficiency". Frontiers in Bioscience. 10 (2): 334–343. doi:10.2741/e825. PMID   29293461.
  10. ↑ Rodriguez KM, Pastuszak AW, Lipshultz LI (August 2016). "Enclomiphene citrate for the treatment of secondary male hypogonadism". Expert Opinion on Pharmacotherapy. 17 (11): 1561–1567. doi:10.1080/14656566.2016.1204294. PMC   5009465 . PMID   27337642.
  11. 1 2 3 Committee for Medicinal Products for Human Use (CHMP) (January 25, 2018). "Assessment report: EnCyzix" (PDF). European Medicines Agency. Retrieved November 7, 2023.
  12. 1 2 Kaminetsky J, Werner M, Fontenot G, Wiehle RD (June 2013). "Oral enclomiphene citrate stimulates the endogenous production of testosterone and sperm counts in men with low testosterone: comparison with testosterone gel". The Journal of Sexual Medicine. 10 (6): 1628–1635. doi:10.1111/jsm.12116. PMID   23530575.
  13. ↑ Wiehle RD, Fontenot GK, Willett MS, Garcia WD, Podolski JS (2014-12-01). "Enclomiphene Citrate Stimulates Serum Testosterone in Men With Low Testosterone Within 14 Days". Journal of Men's Health. 11 (4): 196–205. doi:10.1089/jomh.2014.0006. ISSN   1875-6867.
  14. ↑ Mbi Feh MK, Wadhwa R (2022). "Clomiphene". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID   32644718 . Retrieved 2022-11-29.
  15. ↑ Elsaied M. "Enclomiphene Citrate". Food and Drug Administration .
  16. ↑ Hill S, Arutchelvam V, Quinton R (February 2009). "Enclomiphene, an estrogen receptor antagonist for the treatment of testosterone deficiency in men". IDrugs. 12 (2): 109–119. PMID   19204885.
  17. ↑ Rodriguez KM, Pastuszak AW, Lipshultz LI (August 2016). "Enclomiphene citrate for the treatment of secondary male hypogonadism". Expert Opinion on Pharmacotherapy. 17 (11): 1561–1567. doi:10.1080/14656566.2016.1204294. PMC   5009465 . PMID   27337642.
  18. ↑ Earl JA, Kim ED (May 2019). "Enclomiphene citrate: A treatment that maintains fertility in men with secondary hypogonadism". Expert Review of Endocrinology & Metabolism. 14 (3): 157–165. doi:10.1080/17446651.2019.1612239. PMID   31063005. S2CID   146811440.
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