A review of the physiology behind letrozole applications in infertility: are current protocols optimal?

Abstract

Letrozole is a targeted aromatase inhibitor which has primarily been used in post-menopausal women with breast cancer. Recently, it has been utilized in infertile pre-menopausal women because of its ability to enhance FSH production for ovulation induction. However, the ovarian follicle’s response to FSH is only a part of the endocrine events occurring in a developing follicle. The health of the small antral follicles is driven primarily by androgens, which contribute to granulosa cell mitosis, sensitivity to FSH, and resistance to atresia. In contrast, elevated androgens in the late antral to pre-ovulatory follicle have a negative impact on follicle health and lead to atresia and cystic follicle formation. This ovarian physiologic data suggests that current applications of letrozole to infertility may be squandering some of the primary benefits available in using letrozole to promote follicle development. Four applications of letrozole to infertility that have appeared in the medical literature are reviewed. Androgen-related benefits are reviewed and various questions put forward about how letrozole could be more effectively used to help patients in these settings.

Using Letrozole Cotreatment With Progestin-Primed Ovarian Stimulation In Women With Polycystic Ovary Syndrome Treated For IVF

“…As an aromatase inhibitor, letrozole coadministration results in decreased oestrogens and accumulation of precursors such as progesterone, testosterone as well as 17α-progesterone [12,34,35].Thus, the lower serum E 2 concentration and higher P levels were observed after cotreatment with LE in PPOS protocol. In addition, the accumulation of androgens promotes recruitment of small antral follicles [36,37]. Under the stimulation of exogenous Gn, the number of follicles with diameter >10 mm or >14 mm was signi cantly higher after LE coadministration, and more growing follicles may also result in higher progesterone levels in the late follicular phase during COH.…”

Effects of letrozole co-treatment on outcomes of gonadotropin releasing hormone antagonist cycles in POSEIDON group 3 and 4 expected poor responders

“…Letrozole blocks conversation of androgens to estrogens by competitively inhibiting aromatase enzyme throughout the body that results with decreased estrogen and increased androgen levels [7]. Increase in androgen levels augments FSH activity and androgens are known to take crucial roles in pre-antral to early antral follicle transition [7].…”

“…Letrozole blocks conversation of androgens to estrogens by competitively inhibiting aromatase enzyme throughout the body that results with decreased estrogen and increased androgen levels [7]. Increase in androgen levels augments FSH activity and androgens are known to take crucial roles in pre-antral to early antral follicle transition [7]. Low androgen levels have been shown to be associated with impaired IVF success and transdermal testosterone pre-treatment has been demonstrated to increase live birth rates in poor responder women in previous studies [8,9].…”

“…Unlike clomiphene citrate that depletes estrogen receptors, letrozole left negative estrogen feed-back mechanisms intact, therefore interferes less in the processes of normal follicular development, atresia of smaller follicles and dominant follicle selection hence induces mono-follicular growth that more closely resembles to a natural menstrual cycle and increases the chance of achieving a singleton pregnancy [10]. Besides these, letrozole has a short half-life of 45 minutes [7]. All these factors make letrozole an attractive option in infertility treatments.…”

Ovulation Induction in Patients with Polycystic Ovarian Syndrome (PCOS) & Hyperprolactinemia (HPRL): Efficacy of Letrozole (LE) Combined with Cabergoline (CE) in Comparison to (LE) Alone

“…(LE) is a third-generation aromatase inhibitor. It blocks the conversion of C-19 androgens to C-18 estrogens by competitively inhibiting the enzyme, aromatase (cytochrome P-450), which is an essential step in estrogen biosynthesis in the ovary and other tissues [17]. The subsequent feedback to the hypothalamus containing reduced estrogen levels, triggers a compensatory increase in hypothalamic gonadotropin-releasing hormone (GnRH) secretion, and thus an increased release of pituitary gonadotropins (FSH) & (LH.).…”