Letrozole or Exemestane: What's the Difference

Letrozole and exemestane are two third-generation aromatase inhibitors widely used in oncology. Both sharply reduce estrogen formation, but they do so in fundamentally different ways. The editorial team explains what a ‘reversible’ and an ‘irreversible’ inhibitor means, and how this difference affects the properties of the drugs.

Aromatase and why it should be blocked

Aromatase is an enzyme of the cytochrome P450 family (CYP19A1) that converts androgens into estrogens: androstenedione into estrone, testosterone into estradiol. In women of reproductive age the main source of estrogens is the ovaries, but after menopause estrogens are formed mainly in peripheral tissues: adipose, muscle, skin, and also in the breast tumor itself.

That is precisely why aromatase inhibitors have become a key tool for treating hormone-receptor-positive breast cancer in postmenopausal women. By blocking the enzyme, they deprive the tumor of estrogen stimulus. In premenopausal women aromatase inhibitors on their own are ineffective, because the ovaries respond by increasing estrogen production, so they are combined with suppression of ovarian function.

In men aromatase is responsible for the formation of most estradiol from testosterone. In men estradiol is needed for the bones, lipid metabolism, libido and regulation of the hormonal axis. Blocking aromatase in men raises LH and testosterone, but at the same time deprives the body of estrogen protection of the bones.

Modern third-generation aromatase inhibitors — anastrozole, letrozole and exemestane — are much more selective than their predecessors and have almost no effect on the synthesis of other steroid hormones, in particular cortisol and aldosterone.

Two types of inhibitors: reversible and irreversible

Letrozole is a non-steroidal inhibitor with a triazole ring. It binds to the heme part of aromatase and competitively, reversibly blocks the enzyme. While letrozole is present in the blood, the enzyme is blocked; when the concentration falls, aromatase activity gradually recovers.

Exemestane has a steroidal structure and is an analogue of the natural aromatase substrate — androstenedione. The enzyme ‘accepts’ it as a substrate and begins processing, but the resulting intermediate product binds irreversibly to the active center. This mechanism is called ‘suicide’-type inactivation: the enzyme destroys itself.

The practical consequence: after irreversible inactivation, to restore aromatase activity the body has to synthesize new enzyme molecules. Therefore the effect of exemestane lasts longer than one would expect from its relatively short half-life.

This difference is often simplistically presented as ‘exemestane is stronger’ or ‘letrozole is stronger’. In reality both mechanisms at therapeutic concentrations give deep suppression of the enzyme; what differs is the kinetics of recovery and some additional properties of the molecules.

Pharmacokinetics and strength of suppression

Letrozole is well absorbed when taken orally regardless of food and has a long half-life — about 2 days according to the official label. A steady-state concentration is established after a few weeks of daily intake. It is metabolized in the liver with the participation of CYP3A4 and CYP2A6.

Exemestane has a shorter half-life — about a day. The label recommends taking it after food, since fatty food significantly increases absorption. It is metabolized via CYP3A4, and one of its metabolites, 17-hydroexemestane, has androgenic activity.

According to a randomized crossover study by Geisler et al. (2002), letrozole suppressed total body aromatization by more than 99% and lowered plasma estrogens more strongly than anastrozole. Exemestane also provides deep suppression of aromatization, but there are few direct head-to-head comparisons with letrozole using the same methodology.

For clinical effectiveness, however, what matters is not the fraction of suppression in the laboratory but the results of randomized studies. In the MA.27 study (Goss et al., 2013) exemestane and anastrozole showed comparable effectiveness in adjuvant therapy of breast cancer.

Effect on bones, lipids and androgens

A common consequence of strong estrogen suppression is loss of bone tissue. In postmenopausal women, under aromatase inhibitors bone mineral density decreases and the frequency of fractures increases compared with tamoxifen, as shown, in particular, by the BIG 1-98 study (Thürlimann et al., 2005). Therefore patients undergo densitometry and, if needed, are prescribed drugs to protect the bones.

The steroidal structure of exemestane and the androgenic activity of its metabolite gave grounds for the hypothesis that it harms the bones less. Experimental data in animals partly supported this, but in clinical studies the difference between exemestane and non-steroidal inhibitors regarding fractures did not prove convincing.

Regarding lipids the data are inconsistent: different studies reported minor changes in cholesterol under aromatase inhibitors. In men, suppression of estradiol can lower ‘good’ HDL cholesterol, since estrogens participate in the regulation of lipid metabolism.

In men both drugs raise LH and testosterone, but at the cost of a sharp fall in estradiol. A study by Finkelstein et al. (2013) showed that it is estradiol in men that is responsible for a significant part of the effects previously attributed to testosterone — in particular, the preservation of bone, part of sexual function, and the regulation of fat mass.

Side effects and limitations

The most frequent side effects of aromatase inhibitors in oncology patients are pain in the joints and muscles (arthralgia), hot flashes, fatigue, dryness of the mucous membranes, and loss of bone mass. Arthralgia is one of the main reasons why women stop treatment.

For exemestane, androgenic effects associated with its metabolite are additionally described, and for letrozole, more pronounced estrogen suppression when compared with anastrozole. Whether these differences have clinical significance for a particular patient is decided by the oncologist.

In men, excessive suppression of estradiol manifests as joint pain, decreased libido, worsening mood, and loss of bone mass. In the sports community such situations arise precisely because of an attempt to ‘completely remove estrogen’, which from a medical point of view is a mistake.

• Common risks: loss of bone mass, arthralgia, hot flashes, changes in lipids.
• Letrozole: prolonged presence in the blood, deep suppression of estrogens.
• Exemestane: irreversible inactivation of the enzyme, androgenic metabolite, dependence of absorption on food.
• Both: banned by WADA in section S4 at all times.

Editorial conclusions

Letrozole and exemestane lead to the same goal — a deep reduction of estrogens — by different routes. Letrozole reversibly blocks aromatase and circulates in the blood for a long time; exemestane irreversibly destroys the enzyme, has a steroidal structure and an androgenic metabolite.

In clinical studies of breast cancer, third-generation aromatase inhibitors demonstrate comparable effectiveness, and the choice between them is determined by tolerability, concurrent conditions and the oncologist's experience.

For men the key lesson is that estradiol is a necessary hormone, and its excessive suppression harms the bones, lipids and well-being.

We also recommend reading our materials on for whom doctors prescribe letrozole or exemestane, on the role of estradiol in the male body, and on the comparison of raloxifene with clomiphene.

References

1. 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.
2. Goss PE, Ingle JN, Pritchard KI, et al. Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27 — a randomized controlled phase III trial. J Clin Oncol. 2013;31(11):1398–1404.
3. Breast International Group (BIG) 1-98 Collaborative Group; Thürlimann B, Keshaviah A, Coates AS, et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med. 2005;353(26):2747–2757.
4. Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004;350(11):1081–1092.
5. Finkelstein JS, Lee H, Burnett-Bowie SA, et al. Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med. 2013;369(11):1011–1022.
6. de Ronde W, de Jong FH. Aromatase inhibitors in men: effects and therapeutic options. Reprod Biol Endocrinol. 2011;9:93.
7. World Anti-Doping Agency. Prohibited List. Montreal: WADA (чинна редакція).