Testolactone

Last updated
Testolactone
Testolactone.svg
Clinical data
Trade names Teslac
Other names13-Hydroxy-3-oxo-13,17-secoandrosta-1,4-dien-17-oic acid δ-lactone; SQ-9538; Fludestrin; NSC-12173; NSC-23759
AHFS/Drugs.com Consumer Drug Information
Routes of
administration 		By mouth
Drug class Aromatase inhibitor; Antiestrogen
ATC code
  • none
Pharmacokinetic data
Protein binding ~85%
Metabolism Liver
Excretion Urine
Identifiers
  • (4aS,4bR,10aR,10bS,12aS)-10a,12a-Dimethyl-3,4,4a,5,6,10a,10b,11,12,12a-decahydro-2H-naphtho[2,1-f]chromene-2,8(4bH)-dione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.012.304 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C19H24O3
Molar mass 300.398 g·mol−1
3D model (JSmol)
  • CC12CCC3C(C1CCC(=O)O2)CCC4=CC(=O)C=CC34C
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Testolactone (INN Tooltip International Nonproprietary Name, USAN Tooltip United States Adopted Name) (brand name Teslac) is a non-selective, irreversible, steroidal aromatase inhibitor which is used as an antineoplastic drug to treat advanced-stage breast cancer. [1] [2] [3] [4] The drug was discontinued in 2008 and is no longer available for medical use. [4] [5]

Contents

Medical uses

Testolactone is mainly used for treating various types of breast cancer in women who have been through menopause or whose ovaries no longer function. [6] It works by blocking the production of estrogens, which helps prevent the growth of breast cancers that are stimulated by estrogens. It may also prevent tumor cells from being activated by other hormones. [6] Testolactone has also been used to postpone precocious puberty because of its ability to block estrogen production. [7] In addition, it has been used in the treatment of gynecomastia. [8] [9]

Testolactone is used to treat breast cancer at a dosage of 250 mg four times per day by mouth or 100 mg three times per week by intramuscular injection. [10]

Available forms

Testolactone has been provided in the form of 50 mg and 250 mg oral tablets. [11] [12]

Side effects

The most common side effects include:

Rare but serious side effects include:

Pharmacology

The principal action of testolactone is reported to be inhibition of aromatase activity and the reduction in estrogen synthesis that follows. Androstenedione, a 19-carbon steroid hormone produced in the adrenal glands and the gonads, is where estrone synthesis originates and is the source of estrogen in postmenopausal women. In vitro studies report that the aromatase inhibition may be noncompetitive and irreversible, and could possibly account for the persistence of this drug's effect on estrogen synthesis after drug withdrawal. [2] Testolactone at a dosage of 1,000 mg/day has been found to decrease estradiol levels in men by 25 to 50% after 6 to 10 days of use. [12] This reduction is substantially less than with second- and third-generation aromatase inhibitors. [12]

In addition to its activity as an aromatase inhibitor, testolactone also reportedly possesses some anabolic activity and weak androgenic activity via binding to and activation of the androgen receptor (AR). [4] However, its affinity for the AR is very low; in one study, it showed 0.0029% of the affinity of the anabolic steroid metribolone (100%) for the human AR (Ki = 41 μM and 1.18 nM, respectively). [16] In accordance, androgenic side effects such as hirsutism, acne, and voice changes have been reported in no women in clinical trials with testolactone. [10]

Pharmacodynamics of aromatase inhibitors
GenerationMedicationDosage % inhibitionaClassbIC50c
FirstTestolactone250 mg 4x/day p.o. ?Type I ?
100 mg 3x/week i.m. ?
Rogletimide 200 mg 2x/day p.o.
400 mg 2x/day p.o.
800 mg 2x/day p.o.		50.6%
63.5%
73.8%		Type II ?
Aminoglutethimide 250 mg mg 4x/day p.o.90.6%Type II4,500 nM
Second Formestane 125 mg 1x/day p.o.
125 mg 2x/day p.o.
250 mg 1x/day p.o.		72.3%
70.0%
57.3%		Type I30 nM
250 mg 1x/2 weeks i.m.
500 mg 1x/2 weeks i.m.
500 mg 1x/1 week i.m.		84.8%
91.9%
92.5%
Fadrozole 1 mg 1x/day p.o.
2 mg 2x/day p.o.		82.4%
92.6%		Type II ?
Third Exemestane 25 mg 1x/day p.o.97.9%Type I15 nM
Anastrozole 1 mg 1x/day p.o.
10 mg 1x/day p.o.		96.7–97.3%
98.1%		Type II10 nM
Letrozole 0.5 mg 1x/day p.o.
2.5 mg 1x/day p.o.		98.4%
98.9%–>99.1%		Type II2.5 nM
Footnotes:a = In postmenopausal women. b = Type I: Steroidal, irreversible (substrate-binding site). Type II: Nonsteroidal, reversible (binding to and interference with the cytochrome P450 heme moiety). c = In breast cancer homogenates. Sources: See template.

Chemistry

Testolactone, also known as 13-hydroxy-3-oxo-13,17-secoandrosta-1,4-dien-17-oic acid δ-lactone, is a synthetic 18-oxasteroid and a D-homo-18-oxo analogue of androstenedione (androst-4-en-3,17-dione), with a six-membered lactone ring in place of the five-membered carbocyclic D-ring. [4] [1]

History

Testolactone was first approved for medical use in the United States in 1970. [12]

Related Research Articles

<span class="mw-page-title-main">Androstenedione</span> Endogenous weak androgen

Androstenedione, or 4-androstenedione, also known as androst-4-ene-3,17-dione, is an endogenous weak androgen steroid hormone and intermediate in the biosynthesis of estrone and of testosterone from dehydroepiandrosterone (DHEA). It is closely related to androstenediol (androst-5-ene-3β,17β-diol).

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

Methyltestosterone, sold under the brand names Android, Metandren, and Testred among others, is an androgen and anabolic steroid (AAS) medication which is used in the treatment of low testosterone levels in men, delayed puberty in boys, at low doses as a component of menopausal hormone therapy for menopausal symptoms like hot flashes, osteoporosis, and low sexual desire in women, and to treat breast cancer in women. It is taken by mouth or held in the cheek or under the tongue.

<span class="mw-page-title-main">Nandrolone decanoate</span> Anabolic steroid

Nandrolone decanoate, sold under the brand name ROLON among others, is an androgen and anabolic steroid (AAS) medication which is used primarily in the treatment of anemias and wasting syndromes, as well as osteoporosis in menopausal women. It is given by injection into muscle or fat once every one to four weeks.

<span class="mw-page-title-main">Metandienone</span> Androgen and anabolic steroid

Metandienone, also known as methandienone or methandrostenolone and sold under the brand name Dianabol (D-Bol) among others, is an androgen and anabolic steroid (AAS) medication which is still quite often used because of its affordability and effectiveness for bulking cycles. It is also used non-medically for physique- and performance-enhancing purposes. It is often taken by mouth.

<span class="mw-page-title-main">Aminoglutethimide</span> Group of stereoisomers

Aminoglutethimide (AG), sold under the brand names Elipten, Cytadren, and Orimeten among others, is a medication which has been used in the treatment of seizures, Cushing's syndrome, breast cancer, and prostate cancer, among other indications. It has also been used by bodybuilders, athletes, and other men for muscle-building and performance- and physique-enhancing purposes. AG is taken by mouth three or four times per day.

<span class="mw-page-title-main">Exemestane</span> Breast cancer medication

Exemestane, sold under the brand name Aromasin among others, is a medication used to treat breast cancer. It is a member of the class of antiestrogens known as aromatase inhibitors. Some breast cancers require estrogen to grow. Those cancers have estrogen receptors (ERs), and are called ER-positive. They may also be called estrogen-responsive, hormonally-responsive, or hormone-receptor-positive. Aromatase is an enzyme that synthesizes estrogen. Aromatase inhibitors block the synthesis of estrogen. This lowers the estrogen level, and slows the growth of cancers.

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

Tibolone, sold under the brand name Livial among others, is a medication which is used in menopausal hormone therapy and in the treatment of postmenopausal osteoporosis and endometriosis. The medication is available alone and is not formulated or used in combination with other medications. It is taken by mouth.

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

Trilostane, sold under the brand name Vetoryl among others, is a medication which has been used in the treatment of Cushing's syndrome, Conn's syndrome, and postmenopausal breast cancer in humans. It was withdrawn for use in humans in the United States in the 1990s but was subsequently approved for use in veterinary medicine in the 2000s to treat Cushing's syndrome in dogs. It is taken by mouth.

<span class="mw-page-title-main">Norethisterone</span> Progestin medication

Norethisterone, also known as norethindrone and sold under many brand names, is a progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication is available in both low-dose and high-dose formulations and both alone and in combination with an estrogen. It is used by mouth or, as norethisterone enanthate, by injection into muscle.

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

Formestane, formerly sold under the brand name Lentaron among others, is a steroidal, selective aromatase inhibitor which is used in the treatment of estrogen receptor-positive breast cancer in postmenopausal women. The drug is not active orally, and was available only as an intramuscular depot injection. Formestane was not approved by the United States FDA and the injectable form that was used in Europe in the past has been withdrawn from the market. Formestane is an analogue of androstenedione.

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

Mesterolone, sold under the brand name Proviron among others, is an androgen and anabolic steroid (AAS) medication which is used mainly in the treatment of low testosterone levels. It has also been used to treat male infertility, although this use is controversial. It is taken by mouth.

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

Fluoxymesterone, sold under the brand names Halotestin and Ultandren among others, is an androgen and anabolic steroid (AAS) medication which is used in the treatment of low testosterone levels in men, delayed puberty in boys, breast cancer in women, and anemia. It is taken by mouth.

Hormonal therapy in oncology is hormone therapy for cancer and is one of the major modalities of medical oncology, others being cytotoxic chemotherapy and targeted therapy (biotherapeutics). It involves the manipulation of the endocrine system through exogenous or external administration of specific hormones, particularly steroid hormones, or drugs which inhibit the production or activity of such hormones. Because steroid hormones are powerful drivers of gene expression in certain cancer cells, changing the levels or activity of certain hormones can cause certain cancers to cease growing, or even undergo cell death. Surgical removal of endocrine organs, such as orchiectomy and oophorectomy can also be employed as a form of hormonal therapy.

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. Antiandrogens are sex hormone antagonists which are able to lower the production and the effects that testosterone can have on female bodies.

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

Normethandrone, also known as methylestrenolone or methylnortestosterone and sold under the brand name Metalutin among others, is a progestin and androgen/anabolic steroid (AAS) medication which is used in combination with an estrogen in the treatment of amenorrhea and menopausal symptoms in women. It is taken by mouth.

<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.

Steroidal aromatase inhibitors are a class of drugs that are mostly used for treating breast cancer in postmenopausal women. High levels of estrogen in breast tissue increases the risk of developing breast cancer and the enzyme aromatase is considered to be a good therapeutic target when treating breast cancer due to it being involved in the final step of estrogen biosynthetic pathway and also its inhibition will not affect production of other steroids. Aromatase Inhibitors are classified into two categories based on their structure, nonsteroidal and steroidal; the latter resemble the structure of androstenedione. Steroidal aromatase inhibitors irreversibly inhibit the enzyme by binding covalently to the binding site of aromatase so the substrate cannot access it.

A steroidogenesis inhibitor, also known as a steroid biosynthesis inhibitor, is a type of drug which inhibits one or more of the enzymes that are involved in the process of steroidogenesis, the biosynthesis of endogenous steroids and steroid hormones. They may inhibit the production of cholesterol and other sterols, sex steroids such as androgens, estrogens, and progestogens, corticosteroids such as glucocorticoids and mineralocorticoids, and neurosteroids. They are used in the treatment of a variety of medical conditions that depend on endogenous steroids.

<span class="mw-page-title-main">Nandrolone phenylpropionate</span> Anabolic steroid

Nandrolone phenylpropionate (NPP), or nandrolone phenpropionate, sold under the brand name Durabolin among others, is an androgen and anabolic steroid (AAS) medication which has been used primarily in the treatment of breast cancer and osteoporosis in women. It is given by injection into muscle once every week. Although it was widely used in the past, the drug has mostly been discontinued and hence is now mostly no longer available.

<span class="mw-page-title-main">Non steroidal aromatase inhibitors</span>

Non-Steroidal Aromatase Inhibitors (NSAIs) are one of two categories of aromatase inhibitors (AIs). AIs are divided into two categories, steroidal aromatase inhibitors and non-steroidal aromatase inhibitors that is based on their mechanism of action and structure. NSAIs are mainly used to treat breast cancer in women. NSAIs binding is a reversible process where NSAIs binds to the aromatase enzyme through non-covalent interactions. When aromatase inhibitors (AIs) are used to treat breast cancer the main target is the aromatase enzyme which is responsible for the high estrogen level.

References

  1. 1 2 Milne GW (8 May 2018). Drugs: Synonyms and Properties: Synonyms and Properties. Taylor & Francis. pp. 935–. ISBN   978-1-351-78989-9.
  2. 1 2 Testolactone at DrugBank.ca
  3. ↑ Dunkel L (July 2006). "Use of aromatase inhibitors to increase final height". Molecular and Cellular Endocrinology. 254–255: 207–216. doi:10.1016/j.mce.2006.04.031. PMID   16766117. S2CID   34706246.
  4. 1 2 3 4 Lemke TL, Williams DA (24 January 2012). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 1362–. ISBN   978-1-60913-345-0.
  5. ↑ "Testolactone Advanced Patient Information". Drugs.com. 2022-03-19. Retrieved 2022-07-21.
  6. 1 2 Testolactone facts and comparisons at Drugs.com
  7. ↑ Carel JC, Lahlou N, Roger M, Chaussain JL (2004). "Precocious puberty and statural growth". Human Reproduction Update. 10 (2): 135–147. doi: 10.1093/humupd/dmh012 . PMID   15073143.
  8. ↑ Becker KL (2001). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. pp. 1206–. ISBN   978-0-7817-1750-2.
  9. ↑ Bland KI, Copeland EM, Klimberg VS (9 September 2009). The Breast E-Book: Comprehensive Management of Benign and Malignant Diseases. Elsevier Health Sciences. pp. 162–. ISBN   978-1-4377-1121-9.
  10. 1 2 Lupulescu A (24 October 1990). "Treatment of Hormone Dependent Cancers". Hormones and Vitamins in Cancer Treatment. CRC Press. pp. 57, 64. ISBN   978-0-8493-5973-6.
  11. ↑ Medical Economics (February 1983). Physicians Desk Reference. PDR Network, LLC. pp. 1921, 1963. ISBN   978-0-87489-859-0.
  12. 1 2 3 4 Llewellyn W (2011). Anabolics. Molecular Nutrition Llc. pp. 805–. ISBN   978-0-9828280-1-4.
  13. ↑ Clark RV, Sherins RJ (1989-05-06). "Treatment of men with idiopathic oligozoospermic infertility using the aromatase inhibitor, testolactone. Results of a double-blinded, randomized, placebo-controlled trial with crossover". Journal of Andrology. 10 (3): 240–247. doi: 10.1002/j.1939-4640.1989.tb00094.x . PMID   2663800.
  14. ↑ "Testolactone Uses, Side Effects & Warnings". Drugs.com. Retrieved 2022-03-27.
  15. ↑ "Testolactone Side Effects: Common, Severe, Long Term". Drugs.com. Retrieved 2022-03-27.
  16. ↑ Eil C, Edelson SK (July 1984). "The use of human skin fibroblasts to obtain potency estimates of drug binding to androgen receptors". The Journal of Clinical Endocrinology and Metabolism. 59 (1): 51–55. doi:10.1210/jcem-59-1-51. PMID   6725525.
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