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Testolactone
Testolactone
Testolactone
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Testolactone
Clinical data
Trade namesTeslac
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.comConsumer Drug Information
Routes of
administration		By mouth
Drug classAromatase inhibitor; Antiestrogen
ATC code
  • none
Pharmacokinetic data
Protein binding~85%
MetabolismLiver
ExcretionUrine
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 InfoCard100.012.304 Edit this at Wikidata
Chemical and physical data
FormulaC19H24O3
Molar mass300.398 g·mol−1
3D model (JSmol)
  • C[C@]12CC[C@@]3([H])[C@](CCC4=CC(C=C[C@]34C)=O)([H])[C@]1([H])CCC(O2)=O
 ☒NcheckY (what is this?)  (verify)

Testolactone (INNTooltip International Nonproprietary Name, USANTooltip 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]

Medical uses

[edit]

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

[edit]

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

Side effects

[edit]

The most common side effects include:

  • Abnormal skin sensations
  • Aches of the legs and arms
  • General body discomfort
  • Hair loss
  • Loss of appetite
  • Nausea[13]
  • Redness of the tongue

Rare but serious side effects include:

Pharmacology

[edit]

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
Generation Medication Dosage % inhibitiona Classb IC50c
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

[edit]

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

[edit]

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

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Testolactone

View on Grokipedia
from Grokipedia
Testolactone is a synthetic steroidal antineoplastic agent and a first-generation steroidal , primarily developed for the palliative treatment of advanced or disseminated in postmenopausal women whose disease has progressed following other hormone therapies. Chemically, it features a six-membered ring attached to the of an structure, with the molecular formula C₁₉H₂₄O₃ and a molecular weight of 300.40. Administered orally as 50 mg tablets under the brand name Teslac, it was well-absorbed from the and metabolized in the liver to derivatives that retained the ring, with primary excretion via urine. As an , testolactone exerted its therapeutic effects by noncompetitively and irreversibly blocking the enzyme , thereby inhibiting the conversion of androgens (such as ) to estrogens (such as estrone), which reduced levels in hormone-dependent tissues. This mechanism showed efficacy in approximately 15% of treated postmenopausal patients, manifesting as tumor regression or stabilization, though it lacked androgenic, estrogenic, or progestational activity. The recommended dosage was 250 mg four times daily, with treatment continuation for at least three months unless disease progression occurred, and it was also applicable in premenopausal women with surgically or radiation-induced ovarian function cessation. Beyond , testolactone found off-label applications in pediatric , particularly for managing gonadotropin-independent . In girls with McCune-Albright syndrome, long-term therapy suppressed levels and reduced the frequency of menses, with variable effects on and predicted adult height. Similarly, in boys with familial male-limited (testotoxicosis), it slowed pubertal progression by blocking the conversion of to , often combined with other agents like for better outcomes; measured androgen elevations were artifactual. Studies also explored its use in obese hypogonadal men to boost testosterone by inhibiting estrogen synthesis, though evidence was limited to small trials. Despite its historical utility as a first-generation , testolactone (Teslac) has been discontinued from the market, with no generics available, and is no longer in routine clinical use due to the advent of more selective and potent third-generation inhibitors like and . Contraindications included to the drug and its use in men with , while warnings highlighted risks of hypercalcemia (requiring monitoring) and potentiation of oral anticoagulants. Approved by the FDA in 1969, its development marked an early milestone in targeted endocrine therapy for hormone-sensitive cancers.

Medical uses

Indications

Testolactone is indicated as an adjunctive palliative therapy for advanced or disseminated in postmenopausal women or in premenopausal women whose ovarian function has been terminated, when is deemed appropriate. This use targets estrogen-sensitive tumors by inhibiting steroid activity, thereby reducing estrone synthesis from adrenal and limiting production that fuels tumor growth. Investigational applications of testolactone have included the treatment of , particularly in with other agents like for familial male or in girls with McCune-Albright syndrome exhibiting luteinizing hormone-releasing hormone-independent forms. Clinical studies have demonstrated that testolactone can slow bone maturation and growth rates in these patients, though efficacy varies and long-term outcomes require further evaluation. Limited evidence from randomized trials has explored testolactone for idiopathic oligozoospermic , aiming to improve parameters through inhibition, but results showed no significant changes in sperm output or quality compared to . Testolactone has also been investigated in small trials for treating in obese men, where it increased testosterone levels by inhibiting synthesis, though evidence is limited to short-term studies. These off-label uses highlight testolactone's role in modulating levels, but its application remains investigational with variable clinical benefits.

Dosage and available forms

Testolactone is administered orally at a standard dosage of 250 mg four times daily, totaling 1 g per day, for the palliative treatment of advanced in postmenopausal women or in premenopausal women whose ovarian function has been terminated. The medication is available in the form of oral tablets, each containing 50 mg of testolactone; historically marketed under the brand name Teslac by Bristol-Myers Squibb, with tablets supplied in bottles of 100. Generic versions of testolactone tablets have been discontinued, and the brand Teslac was discontinued in 2008 once inventories were depleted. Therapy with testolactone is typically continued until progression or unacceptable occurs, with a minimum duration of three months required to evaluate response unless clear progression is evident earlier; ongoing monitoring for clinical response is essential during treatment.

Safety profile

Adverse effects

Testolactone is generally well-tolerated, with a low overall incidence of adverse effects reported in clinical use, primarily consisting of mild to moderate gastrointestinal disturbances.

Common Adverse Effects

The most frequently observed side effects involve the gastrointestinal system, including , , anorexia, , , and hot flushes, which have been noted in patients receiving the drug for treatment. of the extremities occurs commonly, while (alopecia) is rare and may be accompanied by nail growth disturbances that resolve without interrupting therapy. These effects are typically self-limiting and do not require discontinuation of treatment in most cases.

Less Common or Serious Adverse Effects

Less common effects include (numbness or tingling in fingers, toes, or face), , general aches in the extremities, increased , and maculopapular (skin rash). Cardiovascular changes such as elevated warrant monitoring during , particularly in patients with preexisting conditions. Serious allergic reactions, including difficulty breathing or swelling, are rare but require immediate medical attention. In historical clinical trials for advanced , gastrointestinal adverse effects were the predominant toxicities, though specific incidence rates were not consistently quantified across studies; overall, severe effects were infrequent and primarily linked to higher doses like 2000 mg/day. No significant endocrine, hepatic, or renal effects have been reported in studies.

Contraindications and precautions

Testolactone is contraindicated in patients with a known to the drug, as severe allergic reactions may occur. It is also contraindicated for the treatment of in men, where alternative therapies are more appropriate. The drug is intended for use only in postmenopausal women with advanced , as inhibitors like testolactone are ineffective in premenopausal women without concurrent ovarian suppression, due to the ovaries' ability to maintain production via increased stimulation. Caution is recommended in patients with a history of , given reports of blood pressure elevation and associated with its use. Additionally, plasma calcium levels should be monitored in patients with bony metastases, as hypercalcemia may develop during treatment. Testolactone is classified as C and should not be used in pregnant women, due to risks of fetal harm observed in ; its safety in mothers and pediatric patients has not been established, and geriatric patients require careful monitoring for reduced renal or hepatic function. Drug interactions with testolactone are minimal, with the primary concern being potentiation of oral anticoagulants, necessitating close monitoring and potential dosage adjustments to avoid bleeding risks. Potential additive -suppressive effects may arise when combined with other aromatase inhibitors or agents that lower levels, though such combinations are rarely used. No significant inhibitory interactions with enzymes have been identified, as testolactone primarily acts as a substrate for without notable induction or inhibition of other isoforms.

Pharmacology

Pharmacodynamics

Testolactone is a non-selective, irreversible steroidal inhibitor of the enzyme, known as 19A1 (CYP19A1). It binds to the enzyme and inactivates it through a noncompetitive mechanism, thereby blocking the final step in where androgens such as and testosterone are converted to estrogens like estrone and , respectively. This inhibition occurs in peripheral tissues, including adipose and adrenal sources, with effects also observed in gonadal tissues. By suppressing activity, testolactone significantly reduces circulating levels, which in turn inhibits the growth of -dependent tumors, such as those in advanced among postmenopausal women. As a first-generation , it exhibits broader effects on steroidogenesis compared to later non-steroidal agents, potentially influencing multiple steps in due to its structural similarity to endogenous steroids. Although structurally related to testosterone, testolactone is a synthetic derivative featuring a six-membered ring attached to the of the structure, and it demonstrates no significant androgenic, estrogenic, or progestogenic activity, with its primary pharmacological effect being anti-estrogenic through blockade.

Pharmacokinetics

Testolactone is well absorbed from the following , though its has not been precisely quantified. Following , testolactone reaches peak plasma concentrations within 1 to 2 hours, with an elimination of approximately 1 to 5 hours, though data are limited. The drug undergoes hepatic to several derivatives, all of which retain the structure; one identified is 4,5-dihydrotestolactone. No major active metabolites have been identified among these derivatives. Testolactone and its metabolites are primarily excreted in the , with some unmetabolized also appearing in this route; additional pharmacokinetic in humans remain limited. The and its metabolites are substantially excreted by the kidneys, necessitating caution in patients with impaired renal function.

Chemistry

Chemical structure and properties

Testolactone is a synthetic steroidal with the molecular formula C19_{19}H24_{24}O3_{3} and a molecular weight of 300.398 g/mol. It is structurally derived from androst-4-ene-3,17-dione and characterized by a six-membered ring fused to the steroid nucleus in place of the typical five-membered carbocyclic D-ring. Testolactone is a white, odorless crystalline solid that exhibits good solubility in ethanol but only slight solubility in water (approximately 27.4 mg/L). Its melting point ranges from 218 °C to 219 °C.

Synthesis

Testolactone is primarily synthesized from androst-4-ene-3,17-dione () through lactonization at the , forming the characteristic six-membered δ-lactone ring via either microbial oxidation or chemical methods. In the microbial route, fungi such as or Cylindrocarpon radicola perform a Baeyer-Villiger-type oxidation on progesterone or , converting the C17 to the δ-lactone with yields around 50%. This involves enzymatic monooxygenases that insert oxygen stereospecifically, preserving the natural configuration and avoiding harsh chemical conditions. Historical methods for testolactone synthesis emerged in the , with the first reported in using microbial of by Cephalosporium species to yield the directly. By the , chemical approaches were developed, employing Baeyer-Villiger oxidation on steroidal precursors like Δ⁴-androstene-3,17-dione with peracids such as or m-chloroperbenzoic acid (m-CPBA) to introduce the ring. For instance, androst-4-ene-3,17-dione is oxidized at the C17 carbonyl, followed by dehydrogenation if needed to form the 1,4-diene system, achieving overall yields of 33–46% from precursors like β-sitosterol. These early chemical syntheses often started from testosterone or dehydroepiandrosterone, involving protection, oxidation, and lactonization steps. Key challenges in testolactone synthesis include ensuring stereospecificity during D-ring lactone formation, as the Baeyer-Villiger reaction must retain the β-orientation at C17 and maintain trans-fused ring junctions inherent to steroids. Chemical methods face scalability issues due to the explosive nature of peracids, prompting safer alternatives like magnesium monoperoxyphthalate (MMPP) for the oxidation step, which provides 98% yield in the final lactonization. Microbial processes, while more environmentally benign, require optimized fermentation conditions for high yields and purity, addressing limitations in large-scale pharmaceutical production.

History

Development and approval

Testolactone was first synthesized in 1953 through chemical methods by Fried and colleagues at and Sons, as part of broader into steroidal compounds derived from androgens and progestogens. Microbial synthesis routes were also developed around this time, utilizing fungi such as Cylindrocarpon radicola to achieve yields of approximately 50% from precursors like dehydroepiandrosterone. Initial biological evaluations focused on its potential in endocrine therapies, leading to early investigations of its effects on steroid metabolism. The compound entered clinical evaluation for in the early , with the first reported studies by Segaloff et al. in 1960 demonstrating objective remissions in patients with advanced disease treated with Δ¹-testolactone. These early trials, conducted primarily in postmenopausal women, showed response rates of around 15-20% in palliative settings, prompting further investigation into its hormonal modulatory effects. Subsequent pivotal trials in the late , including those by Goldenberg et al., reported objective remission rates of 18-28% in advanced cases, supporting its efficacy as an adjunctive therapy and paving the way for regulatory review. Although testolactone's clinical use began without full understanding of its mechanism, its inhibition of —the enzyme converting androgens to estrogens—was identified in 1975 by Siiteri and colleagues through studies on human placental aromatase activity. This discovery provided a mechanistic basis for its estrogen-suppressing effects in estrogen-dependent cancers. The U.S. (FDA) approved testolactone in 1969 for the palliative treatment of advanced in postmenopausal women, marketed under the trade name Teslac by Bristol-Myers Squibb. Approvals followed in other countries, including and several European nations, shortly thereafter, reflecting its established role in endocrine therapy.

Regulatory status and discontinuation

Testolactone, marketed under the brand name Teslac, was classified by the (FDA) as a synthetic antineoplastic agent. It received FDA approval in for clinical use in treating advanced and became available by prescription in the United States in 1970. The drug was dispensed exclusively through prescription channels, with no over-the-counter availability, and generic forms were limited following the expiration of the original brand , though they did not achieve widespread market presence. In February 2008, Bristol-Myers Squibb announced the discontinuation of Teslac (testolactone) 50 mg tablets, citing commercial factors such as declining demand and the emergence of more effective third-generation . Manufacturing ceased, and once existing inventories were depleted, the product was no longer distributed in the United States. The withdrawal was driven by testolactone's relatively weak inhibitory activity on and moderate clinical compared to newer agents, rather than any safety concerns, with no FDA-issued recalls or alerts related to adverse events. Formal withdrawal of the (NDA 016118) was approved by the FDA in July 2011 at the request of the manufacturer. As of 2025, testolactone is no longer commercially available or most global markets, having been fully discontinued without subsequent reintroduction. Its application in investigational or off-label contexts remains exceedingly rare due to the superiority of modern alternatives. Healthcare providers have transitioned to third-generation inhibitors, such as and , which offer enhanced potency and better outcomes in estrogen-dependent management.

References

  1. https://www.accessdata.fda.gov/drugsatfda_docs/label/2003/16118slr023_teslac_lbl.pdf
  2. https://pubmed.ncbi.nlm.nih.gov/8370686/
  3. https://pubmed.ncbi.nlm.nih.gov/9506727/
  4. https://pmc.ncbi.nlm.nih.gov/articles/PMC3143915/
  5. https://www.empr.com/home/news/teslac-tablets-discontinued/
  6. https://pubchem.ncbi.nlm.nih.gov/compound/Testolactone
  7. https://go.drugbank.com/drugs/DB00894
  8. https://www.rxlist.com/teslac-drug.htm
  9. https://pubmed.ncbi.nlm.nih.gov/8421081/
  10. https://academic.oup.com/jcem/article/84/1/175/2866202
  11. https://www.nejm.org/doi/abs/10.1056/NEJM198902233200805
  12. https://www.mdpi.com/2813-2998/2/1/5
  13. https://pubmed.ncbi.nlm.nih.gov/2663800/
  14. https://onlinelibrary.wiley.com/doi/abs/10.1002/j.1939-4640.1989.tb00094.x
  15. https://www.sciencedirect.com/topics/medicine-and-dentistry/testolactone
  16. https://pubmed.ncbi.nlm.nih.gov/14506617/
  17. https://www.drugs.com/dosage/testolactone.html
  18. https://www.drugs.com/cons/testolactone.html
  19. https://www.drugs.com/sfx/testolactone-side-effects.html
  20. https://www.mayoclinic.org/drugs-supplements/testolactone-oral-route/side-effects/drg-20066287
  21. https://www.ncbi.nlm.nih.gov/books/NBK557856/
  22. https://www.researchgate.net/publication/368320845_Testolactone_The_Rise_and_Fall_of_a_Drug
  23. https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/testolactone
  24. https://pubmed.ncbi.nlm.nih.gov/6643639/
  25. https://doi.org/10.1021/ja01118a530
  26. https://doi.org/10.1590/S0103-50532003000600014
  27. https://doi.org/10.1016/j.steroids.2015.02.011
  28. https://pubmed.ncbi.nlm.nih.gov/13749676/
  29. https://www.federalregister.gov/documents/2011/06/08/2011-14164/bristol-myers-squibb-co-et-al-withdrawal-of-approval-of-70-new-drug-applications-and-97-abbreviated
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