The History of the Creation of Letrozole

Letrozole today is one of the standard drugs for hormonal therapy of breast cancer and at the same time a substance that WADA bans for male athletes. To understand why this molecule looks the way it does and why it is judged so strictly, the editorial team traced its path: from fundamental research on estrogens to large randomized trials.

Background: aromatase as a target

The history of letrozole begins not with the molecule itself, but with the question of where estrogen comes from in the body. In the mid-20th century, biochemists established that estrogens are synthesized from androgens - androstenedione and testosterone - with the involvement of a separate enzyme complex. This process was called aromatization, because ring A of the steroid molecule turns into an aromatic ring, and the enzyme itself was later named aromatase (CYP19A1).

In parallel, oncologists accumulated observations that some breast tumors depend on estrogens. As early as the end of the 19th century, surgeons noticed that removing the ovaries sometimes caused regression of breast cancer. In the 20th century this idea was developed: hormone-dependent tumors «feed» on estrogen, so a deficiency of it can slow their growth.

After menopause, the ovaries produce almost no estrogens, yet their synthesis does not stop completely. Fat tissue, muscles, skin, and the tumor itself continue to aromatize androgens of adrenal origin. That is why in postmenopausal women estrogen can be «switched off» in only one way - by blocking aromatase.

A detailed history of these discoveries is described in a review by Santen and colleagues (2009) in Endocrine Reviews. The authors show that the idea of pharmacological blockade of aromatase took shape around the 1970s, when it became clear that surgical removal of the adrenal glands was too traumatic and dangerous a way to lower estrogens.

The first generations of aromatase inhibitors

The first drug that clinically suppressed estrogen synthesis was aminoglutethimide. It was originally created as an anticonvulsant, but it turned out to block several enzymes of steroidogenesis, including aromatase. In effect it caused a «pharmacological adrenalectomy» and required the simultaneous prescription of glucocorticoids.

The low selectivity of aminoglutethimide meant many side effects: drowsiness, rash, impaired adrenal function. So researchers set the task of creating substances that would act selectively on aromatase, without affecting the synthesis of cortisol and aldosterone.

The second generation went along two paths. The group of Angela Brodie developed the steroidal inhibitor formestane, which bound irreversibly to the enzyme but was administered by injection. Other companies worked on nonsteroidal compounds based on imidazole, in particular fadrozole, which was more selective but still not sufficiently so.

It was precisely against the backdrop of these limitations that a race for a third generation began at several pharmaceutical companies - for oral, highly selective, and potent inhibitors that could be taken once a day.

The birth of CGS 20267 in the Ciba-Geigy laboratories

Letrozole was synthesized at the Swiss company Ciba-Geigy (later part of Novartis) under the working code CGS 20267. A key role in its discovery and preclinical study was played by the pharmacologist Ajay Bhatnagar, who later described this history in detail in a 2007 article in Breast Cancer Research and Treatment.

Chemically, letrozole belongs to the triazoles. A nitrogen atom in the triazole ring coordinates with the iron atom in the heme portion of aromatase, competitively and reversibly blocking the enzyme's active site. Two benzonitrile groups provide high affinity specifically for aromatase, rather than for other cytochromes P450.

In preclinical models, CGS 20267 proved to be much more potent than its predecessors and had almost no effect on corticosteroid synthesis. For the developers this meant the main thing: the drug could be prescribed without glucocorticoid replacement therapy, and its action was confined specifically to estrogens.

Early pharmacological studies in humans showed that letrozole lowers the level of circulating estrogens in postmenopausal women by more than 95%. This was later confirmed by a crossover study by Geisler and colleagues (2002), in which letrozole suppressed total aromatization in the body more strongly than anastrozole.

Clinical trials and registration

The first clinical studies of letrozole were conducted in women with advanced hormone-dependent breast cancer whose disease had progressed on tamoxifen. In these comparisons letrozole showed advantages over older second-line drugs, and in the late 1990s it was registered under the trade name Femara.

A real breakthrough came in the 2000s, when the drug began to be studied in early stages of the disease. The MA.17 study (Goss et al., 2003) evaluated letrozole after five years of tamoxifen and was unblinded early (the blinding was lifted) because there were noticeably fewer relapses in the letrozole group. This introduced the concept of «extended adjuvant therapy».

The BIG 1-98 trial (2005) directly compared letrozole and tamoxifen as initial adjuvant therapy in more than 8,000 postmenopausal women. Letrozole reduced the risk of relapse but was associated with more frequent fractures and hypercholesterolemia, whereas tamoxifen was associated with thromboembolism and endometrial pathology.

• MA.17- letrozole as a continuation of treatment after tamoxifen.
• BIG 1-98- letrozole versus tamoxifen as initial adjuvant therapy.
• EBCTCG meta-analysis (2015)- a synthesis of all randomized comparisons of aromatase inhibitors with tamoxifen.

A meta-analysis by the Early Breast Cancer Trialists' Collaborative Group (2015) confirmed that in postmenopausal women aromatase inhibitors as a class are somewhat more effective than tamoxifen in preventing relapse. Since then letrozole has entered international clinical guidelines as one of the basic options for hormonal therapy.

New indications, sport, and the WADA ban

Letrozole's ability to lower estrogens soon interested reproductive specialists. Brief suppression of aromatase at the start of the cycle enhances FSH production by the pituitary and can stimulate ovulation. A large randomized study by Legro and colleagues (2014) showed that in women with polycystic ovary syndrome, letrozole produced more live births than clomiphene.

This indication in most countries remains off-label, that is, not stated in the label, although the 2023 international guideline on PCOS considers letrozole a first-line drug for ovulation induction. Such a history well illustrates how an oncology drug found application in an entirely different field.

In parallel, letrozole came into the field of view of sports pharmacology. In men, blocking aromatase raises testosterone levels through a feedback mechanism, and against the background of androgen use it is applied to control estrogenic effects. That is why the World Anti-Doping Agency included aromatase inhibitors in category S4, «Hormone and metabolic modulators», which is in effect at all times - both in and out of competition.

It should be emphasized that the medical data on the benefits of letrozole concern specific indications and controlled conditions. Extrapolating them to healthy people or athletes is incorrect: a deep estrogen deficiency in men worsens bone health, the lipid profile, and libido.

Editorial conclusions

Letrozole is the result of several decades of research: from the discovery of the aromatization of androgens to the search for selective blockers that do not affect other hormones. The third-generation drug became a technical solution to the problems that aminoglutethimide and the early inhibitors could not handle.

Its place in medicine was determined by the large randomized studies MA.17 and BIG 1-98, and later by meta-analyses. They showed not only its effectiveness but also the price of deep estrogen suppression: effects on bones, joints, and lipids.

The history of letrozole also explains why it is judged strictly outside oncology: the potency of the molecule, which is useful against a tumor, turns into risks in a healthy person.

The editorial team also recommends familiarizing yourself with our materials «Letrozole in women: medical indications», «Tests during the use of Letrozole», and «The history of the creation of Exemestane».

References

1. Santen RJ, Brodie H, Simpson ER, Siiteri PK, Brodie A. History of aromatase: saga of an important biological mediator and therapeutic target. Endocr Rev. 2009;30(4):343–375.
2. Bhatnagar AS. The discovery and mechanism of action of letrozole. Breast Cancer Res Treat. 2007;105(Suppl 1):7–17.
3. Geisler J, Haynes B, Anker G, Dowsett M, Lønning PE. Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over study. J Clin Oncol. 2002;20(3):751–757.
4. Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003;349(19):1793–1802.
5. Breast International Group (BIG) 1-98 Collaborative Group. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med. 2005;353(26):2747–2757.
6. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 2015;386(10001):1341–1352.
7. Legro RS, Brzyski RG, Diamond MP, et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med. 2014;371(2):119–129.
8. World Anti-Doping Agency. The World Anti-Doping Code: International Standard — Prohibited List. Montreal: WADA; чинна редакція.