To the Editor:
I read with great interest the article by Elassar et al. (1) in which they addressed the risk of a premature luteinizing hormone (LH) surge (LH ≥ 10 mIU/mL occurring before the detection of the leading follicle ≥ 18 mm in diameter) in letrozole-gonadotropin (Gn)-antagonist group and suggested that “an early start and possibly a higher dose of the antagonist should be considered when using letrozole.” This is a good concept. But they did not explore the cause. They mentioned “ovaries with diminished ovarian reserve are more prone to a premature LH surge.” However, it is not the cause leading to the high rate of premature LH surge associated with letrozole supplementation.
We agree with an early start of the antagonist after using letrozole. It is because of the risk of a premature LH surge, which is due to the following reason: In theory, letrozole is a third-generation aromatase inhibitor that blocks conversion of androstenedione and T to estrogen in the ovary, and reduces circulating E2 levels. This hypoestrogenic state would contribute to increased follicle-stimulating hormone (FSH) secretion and the development of ovarian follicles by releasing the hypothalamic-pituitary axis from estrogenic negative feedback, and increase LH secretion as well.
A recent article by Kucherov et al. (2) gave firm evidence of this. They reported that the increase in LH pulse amplitude and mean LH level was statistically significant and approximately doubled after letrozole administration. The mean LH pulse amplitude for the letrozole group was more than twice that of the control: 5.1 + 2.8 mIU/mL versus 1.6 + 0.7 mIU/mL (P less than .01). In the study of Elassar et al., the mean baseline LH level was 4.9 + 1.9 mIU/mL. After letrozole administration, it would be more prone to a premature LH surge (LH ≥ 10 mIU/mL) on account of significant increase and double.
Xin Chen, M.D., M.Sc.
Center for Reproductive Medicine
Department of Obstetrics and Gynecology,
Southern Medical University,
Guangzhou, People’s Republic of China
1. Elassar A, Engmann L, Nulsen J, Benadiva C. Letrozole and gonadotropins versus luteal estradiol and gonadotropin-releasing hormone antagonist protocol in women with a prior low response to ovarian stimulation . Fertil Steril 2011; Published online April 25, 2011.
2. Kucherov A, Polotsky AJ, Menke M, Isaac B, McAvey B, Buyuk E et al. Aromatase inhibition causes increased amplitude, but not frequency, of hypothalamic-pituitary output in normal women. Fertil Steril 2011;95:2063-6.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.05.010
To the Editor:
I read the recent article on the comparative study using letrozole and gonadotropins versus luteal estradiol and gonadotropin-releasing hormone antagonist protocol (1). Elassar et al. concluded that “Aromatase inhibitor regimens can be a feasible alternative to the LPG protocol in recurrent low ovarian response” (1).
Based on the study, the efficacy of both protocols might be similar. However, there are some differences. The first difference is in regard to the agents and the second difference is in regard to the total dose of gonadotropins administered and E2 levels. The interesting concern is the implication regarding the comparative cost-effectiveness. It might be expected that the protocol with lower required total dose of gonadotropins might be more effective. However, a further comparative systematic assessment of cost and utility of both protocols is required before there can be a final conclusion.
Viroj Wiwanitkit, M.D.
Bangkhae, Bangkok Thailand
1. Elassar A, Engmann L, Nulsen J, Benadiva C. Letrozole and gonadotropins versus luteal estradiol and gonadotropin-releasing hormone antagonist protocol in women with a prior low response to ovarian stimulation. Fertil Steril. 2011 Apr 22. [Epub ahead of print]
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.05.009
The Authors Respond:
We thank Dr. Chen and Dr. Wiwanitkit for their interest in our manuscript (1).
The comments raised by Dr Chen’s letter to the editor are highly valid, and we agree that oral ovarian stimulation medications (including both clomiphene citrate and aromatase inhibitors) are associated with increased levels of LH that may contribute to premature lutenization. This theory was addressed in prior studies cited in our article (2, 3) where elevated LH levels were found in normo-responder patients. Thus, the referred article (4) reporting the increase in LH pulse amplitude following letrozole administration was not the first. However, not all patients on letrozole experience a premature LH surge. In our study, we suggested other possible mechanisms, as aged ovaries with diminished ovarian reserve are more prone to a premature LH surge, presumably due to reduced production of GnRH-attenuating factor. (5) Irrespective of the mechanism, it’s prudent to follow up the patient’s serum LH levels more closely, and consider an early start of the antagonist administration even at lower estradiol (E2) levels.
We also agree with Dr. Wiwanitkit that cost-effectiveness may be one of the decisive factors when comparing two protocols that yield similar results. Patients on letrozole required less gonadotropins administered (1,6). In our study, patients in the letrozole + gonadotropins protocol (LA) needed an average of 4388 IU of gonadotropins versus 6193 IU used by the luteal phase E2 and GnRH antagonist group (LPG), a difference of 1805 IU that may add US $2,496 to the medication expenses. Moreover, the LPG protocol adds the cost of the E2 patches as well as 3 extra ganirelix injections in the luteal phase prior to start of ovarian stimulation. On the other hand, the LA group required 5 mg tablets of letrozole for 5 days. A comparative systematical analysis on cost shows that the letrozole protocol may result in a cost savings of US $2,668 when compared with the LPG protocol. Thus, aromatase inhibitor based regimen may indeed be a potential preferred stimulation protocol based on cost-effectiveness.
Alyaa Elassar, M.D.
Claudio Benadiva, M.D., H.C.L.D.
The Center for Advanced Reproductive Services
University of Connecticut Health Center
1. Elassar A, Engmann L, Nulsen J, Benadiva C. Letrozole and gonadotropins versus luteal estradiol and gonadotropin–releasing hormone antagonist protocol in women with a prior low response to ovarian stimulation. Fertil Steril; 2011 April 25. [Epub ahead of print]
2. Lee TH, Lin YH, Seow KM, Hwang JL, Tzeng CR, Yang YS. Effectiveness of cetrorelix for the prevention of premature luteinizing hormone surge during controlled ovarian stimulation using letrozole and gonadotropins: a randomized trial. Fertil Steril. 2008; 90:113-20
3. Verpoest WM, Kolibianakis E, Papanikolaou E, Smitz J, Van Steirteghem A, Devroey P. Aromatase inhibitors in ovarian stimulation for IVF/ICSI: a pilot study. Reprod Biomed Online 2006;13:166-72.
4. Kucherov A, Polotsky AJ, Menke M, Isaac B, McAvey B, Buyuk E et al. Aromatase inhibition causes increased amplitude, but not frequency of hypothalamic –pituitary output in normal women. Fertil Steril 2011;95:2063-6.
5. de Ziegler D, Mattenberger C, Schwarz C, Ibecheole V, Fournet N, Bianchi-Demicheli F. New tools for optimizing endometrial receptivity in controlled ovarian hyperstimulation: aromatase inhibitors and LH/(mini)hCG. Ann N Y Acad Sci 2004;1034:262-77.
6. Goswami SK, Das T, Chattopadhyay R, Sawhney V, Kumar J, Chaudhury K, et al. A randomized single-blind controlled trial of letrozole as a low-cost IVF protocol in women with poor ovarian response: a preliminary report. Hum Reprod 2004;19:2031-5.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.05.011