{{Short description|Chemical compound}} {{Drugbox | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 408927562 | IUPAC_name = (4a''S'',4b''R'',10a''R'',10b''S'',12a''S'')-10a,12a-Dimethyl-3,4,4a,5,6,10a,10b,11,12,12a-decahydro-2''H''-naphtho[2,1-''f'']chromene-2,8(4b''H'')-dione | image = Testolactone.svg | image_class = skin-invert-image | width = 225px
<!--Clinical data--> | tradename = Teslac | Drugs.com = {{drugs.com|CDI|testolactone}} | pregnancy_US = C | routes_of_administration = By mouth | class = Aromatase inhibitor; Antiestrogen
<!--Pharmacokinetic data--> | bioavailability = | protein_bound = ~85% | metabolism = Liver | elimination_half-life = | excretion = Urine
<!--Identifiers--> | CAS_number_Ref = {{cascite|correct|CAS}} | CAS_number = 968-93-4 | ATC_prefix = none | PubChem = 13769 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00894 | ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} | ChemSpiderID = 13172 | IUPHAR_ligand = 7303 | UNII_Ref = {{fdacite|changed|FDA}} | UNII = 6J9BLA949Q | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D00153 | ChEBI_Ref = {{ebicite|changed|EBI}} | ChEBI = 9460 | ChEMBL_Ref = {{ebicite|changed|EBI}} | ChEMBL = 1571 | synonyms = 13-Hydroxy-3-oxo-13,17-secoandrosta-1,4-dien-17-oic acid δ-lactone; SQ-9538; Fludestrin; NSC-12173; NSC-23759
<!--Chemical data--> | C=19 | H=24 | O=3 | SMILES = C[C@]12CC[C@@]3([H])[C@](CCC4=CC(C=C[C@]34C)=O)([H])[C@]1([H])CCC(O2)=O }}
'''Testolactone''' ({{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|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.<ref name="Milne2018">{{cite book| vauthors = Milne GW |title=Drugs: Synonyms and Properties: Synonyms and Properties|url=https://books.google.com/books?id=xUlaDwAAQBAJ&pg=PT935|date=8 May 2018|publisher=Taylor & Francis|isbn=978-1-351-78989-9|pages=935–}}</ref><ref name="drugbank">[http://www.drugbank.ca/cgi-bin/getCard.cgi?CARD=DB00894.txt Testolactone] at DrugBank.ca</ref><ref name="pmid16766117">{{cite journal | vauthors = Dunkel L | title = Use of aromatase inhibitors to increase final height | journal = Molecular and Cellular Endocrinology | volume = 254-255 | pages = 207–216 | date = July 2006 | pmid = 16766117 | doi = 10.1016/j.mce.2006.04.031 | s2cid = 34706246 }}</ref><ref name="LemkeWilliams2012" /> The drug was discontinued in 2008 and is no longer available for medical use.<ref name="LemkeWilliams2012" /><ref name="Drugs.com">{{cite web |url= https://www.drugs.com/international/testolactone.html | access-date=2022-07-21 | title=Testolactone Advanced Patient Information | date=2022-03-19 | website=Drugs.com | language=en-us }}</ref>
==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.<ref name=comparison>[https://www.drugs.com/cdi/testolactone.html Testolactone facts and comparisons at Drugs.com<!-- Bot generated title -->]</ref> 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.<ref name=comparison/> Testolactone has also been used to postpone precocious puberty because of its ability to block estrogen production.<ref>{{cite journal | vauthors = Carel JC, Lahlou N, Roger M, Chaussain JL | title = Precocious puberty and statural growth | journal = Human Reproduction Update | volume = 10 | issue = 2 | pages = 135–147 | year = 2004 | pmid = 15073143 | doi = 10.1093/humupd/dmh012 | doi-access = free }}</ref> In addition, it has been used in the treatment of gynecomastia.<ref name="Becker2001">{{cite book| vauthors = Becker KL |title=Principles and Practice of Endocrinology and Metabolism|url=https://books.google.com/books?id=FVfzRvaucq8C&pg=PA1206|year=2001|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-1750-2|pages=1206–}}</ref><ref name="BlandCopeland2009">{{cite book| vauthors = Bland KI, Copeland EM, Klimberg VS |title=The Breast E-Book: Comprehensive Management of Benign and Malignant Diseases|url=https://books.google.com/books?id=1u4x_iGiHNEC&pg=PA162|date=9 September 2009|publisher=Elsevier Health Sciences|isbn=978-1-4377-1121-9|pages=162–}}</ref>
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.<ref name="Lupulescu1990">{{cite book| vauthors = Lupulescu A | chapter = Treatment of Hormone Dependent Cancers |title=Hormones and Vitamins in Cancer Treatment| chapter-url = https://books.google.com/books?id=VddUa-2cp-YC&pg=PA57 |date=24 October 1990|publisher=CRC Press|isbn=978-0-8493-5973-6|pages=57, 64}}</ref>
===Available forms=== Testolactone has been provided in the form of 50 mg and 250 mg oral tablets.<ref name="Economics1983">{{cite book|author=Medical Economics|title=Physicians Desk Reference|url=https://books.google.com/books?id=RgzoZNdxeUsC|date=February 1983|publisher=PDR Network, LLC|isbn=978-0-87489-859-0|pages=1921, 1963}}</ref><ref name="Llewellyn2011" />
==Side effects== The most common side effects include:
* Abnormal skin sensations * Aches of the legs and arms * General body discomfort * Hair loss * Loss of appetite * Nausea<ref>{{cite journal | vauthors = Clark RV, Sherins RJ | title = Treatment of men with idiopathic oligozoospermic infertility using the aromatase inhibitor, testolactone. Results of a double-blinded, randomized, placebo-controlled trial with crossover | journal = Journal of Andrology | volume = 10 | issue = 3 | pages = 240–247 | date = 1989-05-06 | pmid = 2663800 | doi = 10.1002/j.1939-4640.1989.tb00094.x | doi-access = free }}</ref> * Redness of the tongue
* Vomiting<ref>{{Cite web |title=Testolactone Uses, Side Effects & Warnings |url=https://www.drugs.com/mtm/testolactone.html |access-date=2022-03-27 |website=Drugs.com |language=en}}</ref>
Rare but serious side effects include:
* Allergic reactions * New breast lumps * Bone pain * Menstrual changes, abnormal vaginal bleeding, abnormal vaginal discharge, pelvic pain or pressure * Excessive nausea, vomiting, or thirst * Glossitis * Edema * Paresthesia * Erythema * Alopecia<ref>{{Cite web |title=Testolactone Side Effects: Common, Severe, Long Term |url=https://www.drugs.com/sfx/testolactone-side-effects.html |access-date=2022-03-27 |website=Drugs.com |language=en}}</ref>
==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.<ref name=drugbank/> 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.<ref name="Llewellyn2011">{{cite book| vauthors = Llewellyn W |title=Anabolics|url=https://books.google.com/books?id=afKLA-6wW0oC&pg=PT805|year=2011|publisher=Molecular Nutrition Llc|isbn=978-0-9828280-1-4|pages=805–}}</ref> This reduction is substantially less than with second- and third-generation aromatase inhibitors.<ref name="Llewellyn2011" />
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).<ref name="LemkeWilliams2012">{{cite book| vauthors = Lemke TL, Williams DA |title=Foye's Principles of Medicinal Chemistry|url=https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA1362|date=24 January 2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-60913-345-0|pages=1362–}}</ref> 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 (K<sub>i</sub> = 41 μM and 1.18 nM, respectively).<ref name="pmid6725525">{{cite journal | vauthors = Eil C, Edelson SK | title = The use of human skin fibroblasts to obtain potency estimates of drug binding to androgen receptors | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 59 | issue = 1 | pages = 51–55 | date = July 1984 | pmid = 6725525 | doi = 10.1210/jcem-59-1-51 }}</ref> In accordance, androgenic side effects such as hirsutism, acne, and voice changes have been reported in no women in clinical trials with testolactone.<ref name="Lupulescu1990" />
{{Pharmacodynamics of aromatase inhibitors}}
==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 <small>D</small>-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.<ref name="LemkeWilliams2012" /><ref name="Milne2018"/>
==History== Testolactone was first approved for medical use in the United States in 1970.<ref name="Llewellyn2011" />
== References == {{Reflist}}
{{Chemotherapeutic agents}} {{Estrogens and antiestrogens}} {{Androgen receptor modulators}}
Category:Withdrawn drugs Category:Androgens Category:Androstanes Category:Aromatase inhibitors Category:Enones Category:Hormonal antineoplastic drugs Category:Delta-lactones