Effects of a single 20 mg dose of letrozole on ovarian function post dominant follicle selection: an exploratory randomized controlled trial

Abstract

Background: Our objective was to explore the impact of a single dose of an aromatase inhibitor (letrozole) administered at defined times of the follicular phase or immediately after ovulation on dominant follicle development, luteogenesis and new follicle wave emergence.

Methods: A prospective pilot study using a randomized complete block, controlled, open label design was conducted at an academic clinical research center. Forty-five healthy, female volunteers (25.5 ± 0.9 years, BMI 25.0 ± 0.6 kg/m²) who had not taken hormonal contraceptives for a minimum of 2 months were recruited. A 20 mg dose of Letrozole was administered once orally in each of 3 groups when the dominant follicle reached a diameter of 1) 12 mm, 2) 18 mm, 3) the first day following ovulation (post-ovulation), or 4) treatment was withheld (control). Serial ultrasonography and phlebotomy began on day 4 of the menstrual cycle and continued for 1.5 menstrual cycles. Participants recorded menses and daily events in a life events calendar for the duration of the study. Demographic and single point measurements were compared among groups by ANOVA. Changes in hormone concentrations over time were compared among groups by repeated measures ANOVA. Kruskal-Wallis tests were used for non-normally distributed data.

Results: The dominant follicle in all treatment groups ovulated. There were no differences among experimental groups in peak follicle diameter, follicular growth rate, endometrial thickness at ovulation or inter-ovulatory interval. Plasma concentrations of estradiol dropped, while FSH and LH concentrations rose following treatment in all treatment groups. Plasma FSH and LH concentrations were higher in the 18 mm group compared to the 12 mm and post-ovulation groups (P < 0.02).

Conclusion: Administration of a single 20 mg dose of Letrozole at the times of the menstrual cycle we examined did not induce dominant follicle regression or failure of corpus luteum formation. Letrozole-induced suppression of estradiol synthesis by the dominant follicle was not detrimental to follicle growth or ovulation following follicle selection, likely due to increased circulating concentrations of FSH and LH resulting from a lack of estradiol-induced suppression of the hypothalamic-pituitary-ovarian axis.

Trials registration number: Clinical trials registration number NCT01046578 .

Keywords: Aromatase inhibitor; Endometrium; Estradiol; Follicular phase; Ovulation.

Fig. 1

Schematic diagram of the study protocol

Fig. 2

Flow of participants through the study from enrollment to data analysis

Fig. 3

Mean follicle diameter profiles of the treatment groups. The 12 mm group (n = 10; a), 18 mm group (n = 10; b), post-OV group (n = 10; c), and control group (n = 11; d) are shown separately. Data are shown for 9 days following ovulation and are centralized to the day of treatment for each respective treatment group or day of OV in the control group

Fig. 4

Change in estradiol, FSH and LH over the observation interval. a Mean changes in E₂ concentration over the observation interval in the treatment groups (day 1 = day of treatment). b Mean changes in FSH concentration over the observation interval (day 1 = day of treatment) in the treatment groups. c Mean changes in LH concentration over the observation interval (day 1 = day of treatment) in the treatment groups. Differences among treatment groups are identified within days (P < 0.05). * Within day comparisons among experimental groups. N = 10 for 12 mm, 18 mm and post-OV groups

Fig. 5

Mean profiles of endometrial thickness. Women in all treatment groups, 12 mm (n = 10), 18 mm (n = 10), 24 h post ovulation (n = 10), and control (n = 11) are identified. Data are shown for one inter-menstrual interval and are centralized to the day of ovulation. No significant effect of day was observed for endometrial thickness