To the Editor:
We read with great interest the manuscript by Parsanezhad et al. (1), which reports the results of a prospective, multicenter, randomized, assessor-blind trial comparing the effects of letrozole and triptorelin on uterine myoma volume. The investigators should be congratulated on their observation that the administration of letrozole reduced myoma volume without determining systemic hypoestrogenism. We would like to bring to your attention some details of the study, which may be relevant in the understanding of the use of aromatase inhibitors in premenopausal women.
Letrozole was administered orally at the standard dose of 2.5 mg/day starting the treatment regardless of the day of the menstrual period. Although all the patients were premenopausal, the authors reported that a “nonsignificant follicular growth” was observed in patients receiving letrozole. This finding is apparently in contrast with previous observations. Administration of letrozole to cycling female rats caused a dose dependent inhibition of uterine weight and a statistically significant increase in ovarian weight (2). The daily oral administration of letrozole 2.5 mg and desogestrel 75 μg (started on the second day of the menstrual cycle) to 12 premenopausal women with endometriosis determined the development of functional ovarian cysts in all the study subjects after 2 to 4 months of treatment. The mean (± SD) diameter of these ovarian cysts was 5.0 (± 1.3 cm) with a range between 3.5 and 8.0 cm (3). A significant increase in ovarian volume was also observed in 16 premenopausal women with symptomatic uterine myomas treated with letrozole monotherapy (5 mg/day) for 3 months; nine patients (56.3%) developed follicle cysts (4). It is possible that starting the administration of aromatase inhibitors in the early follicular phase may promote the enlargement of the ovaries and development of functional ovarian cysts. Therefore, Parsanezhad et al. should declare in which phase of the menstrual cycle letrozole therapy was started and whether this was correlated with the development of functional ovarian cysts.
It is well known that some adverse effects may occur during treatment with aromatase inhibitors including arthralgia, myalgia and hair loss (3-5), which are believed to be caused by estrogen deprivation. These adverse effects may have variable severity and, if mild, they may not be declared by the patients or determine the interruption of treatment. In the population analyzed by Parsanezhad et al., the short length of treatment and the absence of hypoestrogenism may have prevented the development of adverse effects. However, it would be interesting to know whether the presence of these adverse effects was systematically investigated during the study.
Simone Ferrero, Ph.D.
Pier Luigi Venturini, M.D.
Valentino Remorgida, M.D.
Department of Obstetrics and Gynecology
San Martino Hospital and University of Genoa
1. Parsanezhad ME, Azmoon M, Alborzi S, Rajaeefard A, Zarei A, Kazerooni T, et al. A randomized, controlled clinical trial comparing the effects of aromatase inhibitor (letrozole) and gonadotropin-releasing hormone agonist (triptorelin) on uterine leiomyoma volume and hormonal status. Fertil Steril (in press)
2. Sinha S, Kaseta J, Santner SJ, Demers LM, Bremmer WJ, Santen RJ. Effect of CGS 20267 on ovarian aromatase and gonadotropin levels in the rat. Breast Cancer Res Treat 1998;48:45-51.
3. Remorgida V, Abbamonte LH, Ragni N, Fulcheri E, Ferrero S. Letrozole and desogestrel-only contraceptive pill for the treatment of stage IV endometriosis. Aust N Z J Obstet Gynaecol 2007;47:222-5.
4. Gurates B, Parmaksiz C, Kilic G, Celik H, Kumru S, Simsek M. Treatment of symptomatic uterine leiomyoma with letrozole. Reprod Biomed Online 2008;17:569-74.
5. Ferrero S, Camerini G, Seracchioli R, Ragni N, Venturini PL, Remorgida V. Letrozole combined with norethisterone acetate compared with norethisterone acetate alone in the treatment of pain symptoms caused by endometriosis. Hum Reprod 2009;24:3033-41.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2010.01.072
The Authors Respond:
We would like to thank Drs. Ferrero , Venturuni and Remorgida for their thoughtful letter. The main points of their letter were observation of the nonsignificant follicular growth and absence of ovarian enlargement in patients receiving letrozole (1).
As we pointed out in our article, it is widely accepted that administration of letrozole starting at early follicular phase would result in follicular growth (2). We treated uterine myoma with oral administration of letrozole 2.5 mg, regardless of the day of menstrual cycle. It seems that cyclic letrozole administration would result in follicular growth (3).
Our statistical methods covered all numbers with a certain degree of variation whose average was statistically significant. That means although there was some growth in some cases, analysis did not show that growth to be statistically significant.
Remorgida and coworkers started a combination of Letrozole 2.5 mg and desogestrel 75 µg on the second day of the cycle (4). They reported the development of ovarian cyst after 2 to 4 months. In another study, Gurates reported an increase in ovarian size (5). As Ferrero and coworkers pointed out in their letter, these treatment protocols differ from ours in several ways, including dose, duration, and day of cycle on which medication was started.
Although our protocol is different from others, we think that the day of administration and duration of treatment are the most important reasons for the absence of significant ovarian cyst and ovarian enlargement.
Mohammad Ebrahim Parsanezhad, M.D.
Shiraz University of Medical Sciences
1. Parsanezhad ME, Azmoon M, Alborzi S, Rajaeefard A, Zarei A, Kazerooni T, et al. A randomized, controlled clinical trial comparing the effects of aromatase inhibitor (letrozole) and gonadotropin-releasing hormone agonist (triptorelin) on uterine leiomyoma volume and
hormonal status. Fertil Steril (in press)
2. Mitwally MF, Casper RF. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate. Fertil Steril 2001;75:305–9.
3. Requena A, Herrero J, Landeras J, Navarro E, Neyro JL, Salvador C. Use of letrozole in assisted reproduction: a systematic review and meta-analysis. Human Reproduction Update 2008; 14:571–82.
4. Remorgida V, Abbamonte LH, Ragni N, Fulcheri E, Ferrero S. Letrozole and desogestrel-only contraceptive pill for the treatment of stage IV endometriosis. Aust N Z J Obstet Gynaecol 2007;47:222-5.
5. Gurates B, Parmaksiz C, Kilic G, Celik H, Kumru S, Simsek M. Treatment of symptomatic uterine leiomyoma with letrozole. Reprod Biomed Online 2008;17:569-74.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2010.01.071