Letrozole is a potent third-generation reversible aromatase inhibitor (AI) widely used in the treatment of postmenopausal women with metastatic breast cancer. This treatment, usually carried out at a dose of 2.5-5.0 mg / day, allows you to achieve optimal suppression of serum estrogen levels and almost no side symptoms. Letrozole’s ability to effectively lower estrogen levels can be used to temporarily counteract the negative feedback effect of estrogen on the hypothalamus and thereby stimulate follicle-stimulating hormone (FSH) secretion.
When taken orally in doses of 1-5 mg/day, letrozole and anastrozole reduce estrogen levels by 97-99%. Due to a significant decrease in circulating estrogen levels in the peripheral blood, AIs are a promising treatment not only for estrogen-dependent diseases, but their use in the early follicular phase of the menstrual cycle may also increase the release of estrogens. gonadotropic hormones. , leading to follicle growth and ovulation in infertile patients. Although letrozole is widely used as an ovulation inducer, it is still “off label”.
The purpose of this review is to assess the results of using letrozole AI as an ovulation induction drug.
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Letrozole or clomiphene citrate? What to choose ?
For a long time, clomiphene citrate (CC) has been used as a first-line drug for the treatment of patients with polycystic ovary syndrome (PCOS). The main disadvantages of using CC are: CC blocks estrogen receptors (ER) throughout the body, while reducing endometrial receptivity, has a long half-life, and has a cumulative property.
In the 1990s, an alternative to CC was found as an ovulation inducer. R. Casper and M. Mitwally first announced the concept of using AI for ovulation induction.
The blocking of the conversion of androgens into estrogens by AIs has two consequences: a decrease in the level of circulating and locally acting estrogens and an increase in the level of intraovarian androgens. A decrease in estrogen levels removes the negative feedback block of estrogen in the hypothalamic-pituitary system. Therefore, it increases the increase in FSH, which results in the growth of follicles. Thus, the negative feedback mechanism remains intact, with normal follicular growth, selection of dominant follicles, atresia of smaller follicles, ultimately leading to monofollicular growth and ovulation.
Another possible mechanism of action of AIs on follicular growth is an increase in the level of intra-ovarian androgens. This seems to increase the sensitivity of the follicles to the action of FSH. Recent studies have shown an important role of androgens in the development of early folliculogenesis events. Androgens increase the number of FSH receptors and stimulate the production of insulin-like growth factor (IGF-I), while FSH and IGF-I act as synergists to promote follicle growth.
Therefore, in summary, AIs have the following advantages over CCs: they do not block ERs in the body; keep the hypothalamic-pituitary arch intact; they have a short period of action (half-life ≈45 h). Such pharmacodynamics of letrozole contributes to an increase in endometrial thickness, quality of cervical mucus, monofollicular growth and better folliculogenesis. Therefore, these factors can lead to a higher pregnancy rate and a higher risk of a singleton pregnancy. Although Letrozole creates an estrogen-deficient environment, the fact that it has no negative effect on the endometrium and cervix is due to the short half-life of the drug.
Over the past 15 years, since the first few publications, letrozole has been widely accepted as an ovulation inducer. Many original articles, reviews and meta-analyses have been published on this topic. Especially in women who failed or were resistant to CC, letrozole proved to be very effective in terms of ovulation rate and live birth rate.
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AI in the treatment of infertility
AIs and in particular letrozole offer new perspectives in the induction of ovulation in women with anovulatory infertility. They have demonstrated their usefulness in the treatment of unexplained infertility and in women with low ovarian reserve. Additionally, the efficacy of using AIs for the control of ovarian hyperstimulation and in the treatment of infertility complicated by endometriosis is discussed.
After the first report by R. Casper and M. Mitwally, Letrozole gradually became the focus of researchers and physicians for the correction of various estrogen-dependent conditions in gynecology and reproduction.
Letrozole, as an ovulation inducer, is most commonly used in three situations: ovulation induction in PCOS; ovulation induction during intrauterine insemination (IUI); ovarian stimulation for IVF/ICSI.