Testolactone

Testolactone (INN, USAN) (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] However, it has been reported to still be marketed in the United States by Bristol-Myers Squibb under the brand name Teslac.[5]

Testolactone

Clinical data
Trade names	Teslac
Other names	13-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
Pregnancy category	US: C (Risk not ruled out)
Routes of administration	By mouth
Drug class	Aromatase inhibitor; Antiestrogen
ATC code	none
Pharmacokinetic data
Protein binding	~85%
Metabolism	Liver
Excretion	Urine
Identifiers
IUPAC name (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	968-93-4^Y
PubChem CID	13769
IUPHAR/BPS	7303
DrugBank	DB00894^Y
ChemSpider	13172^N
UNII	6J9BLA949Q
KEGG	D00153^Y
ChEBI	CHEBI:9460^N
ChEMBL	ChEMBL1571^N
CompTox Dashboard (EPA)	DTXSID2023644
ECHA InfoCard	100.012.304
Chemical and physical data
Formula	C19H24O3
Molar mass	300.398 g·mol^−1
3D model (JSmol)	Interactive image
SMILES CC12CCC3C(C1CCC(=O)O2)CCC4=CC(=O)C=CC34C
^NY (what is this?)  (verify)

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:

• Abnormal skin sensations
• Aches of the legs and arms
• General body discomfort
• Hair loss
• Loss of appetite
• Nausea
• Redness of the tongue
• Vomiting

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 testosterone 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 (K_i = 41 μM and 1.18 nM, respectively).[13] 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

Generation	Medication	Dosage	% inhibition^a	Class^b	IC50^c
First	Testolactone	250 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 II	4,500 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 I	30 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 I	15 nM
	Anastrozole	1 mg 1x/day p.o. 10 mg 1x/day p.o.	96.7–97.3% 98.1%	Type II	10 nM
	Letrozole	0.5 mg 1x/day p.o. 2.5 mg 1x/day p.o.	98.4% 98.9%–>99.1%	Type II	2.5 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]

References

1. George W.A Milne (8 May 2018). Drugs: Synonyms and Properties: Synonyms and Properties. Taylor & Francis. pp. 935–. ISBN 978-1-351-78989-9.
2. Testolactone at DrugBank.ca
3. Dunkel L (July 2006). "Use of aromatase inhibitors to increase final height". Mol. Cell. Endocrinol. 254-255: 207–16. doi:10.1016/j.mce.2006.04.031. PMID 16766117.
4. Thomas L. Lemke; David A. Williams (24 January 2012). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 1362–. ISBN 978-1-60913-345-0.
5. https://www.drugs.com/international/testolactone.html
6. Testolactone facts and comparisons at Drugs.com
7. Carel, J.-C.; Lahlou, N; Roger, M; Chaussain, JL (2004). "Precocious puberty and statural growth". Human Reproduction Update. 10 (2): 135–47. doi:10.1093/humupd/dmh012. PMID 15073143.
8. Kenneth L. Becker (2001). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. pp. 1206–. ISBN 978-0-7817-1750-2.
9. Kirby I. Bland; Edward M. Copeland; V. Suzanne Klimberg (9 September 2009). The Breast E-Book: Comprehensive Management of Benign and Malignant Diseases. Elsevier Health Sciences. pp. 162–. ISBN 1-4377-1121-9.
10. Aurel Lupulescu (24 October 1990). 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. William Llewellyn (2011). Anabolics. Molecular Nutrition Llc. pp. 805–. ISBN 978-0-9828280-1-4.
13. Eil C, Edelson SK (July 1984). "The use of human skin fibroblasts to obtain potency estimates of drug binding to androgen receptors". J. Clin. Endocrinol. Metab. 59 (1): 51–5. doi:10.1210/jcem-59-1-51. PMID 6725525.