Five-day anastrozole in infertility needs supplemental hCG

19 05 2011

To the Editor:

I read with great interest the article by Tredway D et al. (1), in which they concluded that “in terms of ovulation rates, 5-day anastrozole at 1,5, and 10 mg/d was less effective than CC at 50mg/d for cycle 1”. They have done a good work.

However, surprisingly, the ovulation rates for anastrozole groups were obviously low. In their Results Section, they mentioned that “most patients receiving anastrozole 1 mg/d (72.7%) and 5 mg/d (73.5%) achieved monofollicular development (one follicle ≥ 17 mm in diameter), compared with 70.4% of patients receiving CC”. We argue that monofollicular development (one follicle ≥ 17 mm in diameter) rates were similar between anastrozole and CC, why was ovulation rates difference so significant (the ovulation rates for anastrozole at 1, 5, and 10 mg/d were 30.4%, 36.8% and 35.9%, respectively, compared with 64.9% for CC at 50 mg/d)?

We believe that it is due to lack of supplemental hCG.

Anastrozole is a highly selective nonsteroidal aromatase inhibitor(AI) which blocks conversion of androstenedione and T to estrogen in the ovary, and reduce circulating E2 levels. This hypoestrogenic state would contribute to increase FSH secretion and the development of ovarian follicles by releasing the hypothalamic-pituitary axis from estrogenic negative feedback, and increase LH secretion as well.
Wu H et al. (2) reported that the AI (anastrozole) group has a higher LH level, but a lower estrodiol level in stimulation cycle compared with CC group. Further, a recent article by Kucherov A et al.(3) reported that the increase in amplitude and mean LH was statistically significant and approximately doubled after AI (letrozole) administration. The mean LH level of the letrozole group was more than twice that of the control: 9.4 + 3.5 mIU/mL versus 3.4 + 0.7 mIU/mL (P<.01). Moreover, Shapiro BS et al.(4) reported that endogenous LH surge exceeding the equivalent of 52 mIU/mL was associated with good outcome, otherwise the oocyte yield and maturity was lower. Therefore, AI is associated with a high rate of premature LH surge, but it is not high enough to trigger ovulation.

On the other hand, Bedaiwy MA et al. (5) demonstrated that AIs were capable of block the estrogen surge associated with GnRHa. This reduces the possibility of estrogen positive feedback which is pivotal to stimulate LH surge required for ovulation.

In clinical study, as the authors mentioned, Badawy A et al.(6)reported that ovulation rate was 67.9% in the anastrozole group and 68.6% in the CC group respectively without significant difference. Comparing the study of Badawy A et al. with the study of Tredway D et al., hCG was the only known predisposing factor for the higher ovulation rate in the anastrozole group.

In addition, improvement of ovulation rates may contribute to the observed efficacy of anastrozole compared with CC in stimulation cycle. Because the main index for efficacy of stimulation regimen is pregnancy rate even live birth rate, of which the precondition is ovulation.

Xin Chen, M.D., M.Sc.
Center for Reproductive Medicine
Department of Obstetrics and Gynecology,
Nanfang Hospital
Southern Medical University
Guangzhou, People’s Republic of China

References
1. Tredway D, Schertz JC, Bock D, Hemsey G, Diamond MP. Anastrozole vs. clomiphene citrate in infertile women with ovulatory dysfunction: a phase II, randomized, dose-finding study. Fertil Steril 2011;95:1720-4.

2. Wu H, Chen P, Wang NM, Cheng M, Yeh G, Lin K. Comparison of the Ovulation Induction and Hormone Profile Between Anastrozole and Clomiphene Citrate in Women With Infertility. Fertil Steril 2005;84(Suppl 1):S324.

3. 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.

4. Shapiro BS, Daneshmand ST, Restrepo H, Garner FC, Aguirre M, Hudson C.Efficacy of induced luteinizing hormone surge after “trigger” with gonadotropin-releasing hormone agonist. Fertil Steril. 2011 ;95:826-8.

5. Bedaiwy MA, Mousa NA, Casper RF.Aromatase inhibitors prevent the estrogen rise associated with the flare effect of gonadotropins in patients treated with GnRH agonists. Fertil Steril. 2009 ;91:1574-7.

6. Badawy A, Abdel Aal I, Abulatta M. Clomiphene citrate or anastrozole for ovulation induction in women with polycystic ovary syndrome? A prospective controlled trial. Fertil Steril 2009;92:860–3.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.05.058

The Authors Respond:

For the reasons noted in the letter to the editor, we had considered Dr Chen’s suggestion that the difference in ovulation rates between anastrozole and clomiphene citrate was due to the lack of supplemental hCG which was used to induce ovulation in the study by Bedawy et al. (1). However, as noted in the full publications of the five-day anastrozole (2) and single-dose anastrozole trials (3), frequent follicular ultrasound and serum estrogen monitoring was done in all 466 subjects since these were phase II drug development studies. This monitoring revealed no unruptured follicular development or any follicular development in subjects who did not have an LH surge. In fact, ovulation was induced with a spontaneous endogenous LH surge, and adequate luteal progesterone levels were observed in ovulatory patients with follicular development. Consequently supplemental hCG would not have resulted in increased ovulatory rates since no incomplete follicular development from the recruitment phase occurred.

We appreciate Dr Chen’s appealing suggestion, but as discussed in the editorial (4), the monitoring data does not substantiate that the lower ovulation rate was due to the lack of supplemental hCG.

Donald R Tredway, M.D., Ph.D.
Tredway Consulting, LLC

Joan C Schertz, M.Sc.
EMD Serono, Inc.
Rockland, Maryland

References
1. Badawy A, Abdel Aal I, Abulatta M. Clomiphene citrate or anastrozole for ovulation induction in women with polycystic ovary syndrome? A prospective controlled trial. Fertil Steril 2009;92:860–3.

2. Tredway D, Schertz JC, Bock D, Hemsey G, Diamond MP. Anastrozole vs. clomiphene citrate in infertile women with ovulatory dysfunction: a phase II, randomized, dose-finding study. Fertil Steril 2011;95:1720-4.

3. Tredway D, Schertz JC, Bock D, Hemsey G, Diamond MP. Anastrozole single-dose protocol in women with oligo- or anovulatory infertility: result of a randomized phase II dose-response study. Fertil Steril 2011;95:1725-9.

4. Tredway D, Schertz JC. Anastrozole versus clomiphene citrate: which is better for ovulation induction? Fertil Steril 2011;95:1749-51.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.05.059

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