To the Editor:
We read with great interest the paper published recently by Elizur et al. in the September 2009 edition of Fertility and Sterility (1). The authors compared retrospective data of two different protocols used to perform in vitro maturation treatment (IVM) based on physician preference: only micronized 17β-estradiol (6-12 mg/day) for endometrial preparation or human menopausal gonadotropins (HMG) 150 IU/day to induce both endometrial preparation and mild follicle stimulation. Both protocols started between day 6-10 of the cycle and the main outcome measure was the endometrial thickness before oocyte retrieval. We would like to congratulate the authors: we believe that endometrial receptivity is concerning in IVM treatment and studies trying to improve implantation rates should also have the endometrium as target.
However, the authors did not include in the discussion section one study that also evaluated two different endometrial preparations proposed for IVM in PCOS women: starting estradiol 14 days after the menstruation (the planned day of oocyte retrieval: 6 mg/day or 10 mg if endometrial thickness less than 5 mm) or a sequentially increasing dosage of estradiol beginning on the first day of menstrual flow (2 mg/day for 4 days, 4 mg/day for 4 days and then 6 mg/day) (2). Using estradiol since the beginning of the menstrual cycle all women achieved an endometrial thickness greater than 8 mm and the endometrial thickness on the day 14 was 9.96 ± 2.22mm; which is considerably higher than the observed in the two groups on the study of Elizur et al. (1): 7.7 ± 1.8mm and 7.3 ± 1.7 (HMG and estradiol groups). Since the main outcome measure was the endometrial thickness, this previous report should be considered.
A recent publication by Zhao et al. (3) also demonstrated better results in IVM cycles when using estradiol since the beginning of the cycle (days 3-5): the endometrial thickness on the day of embryo transfer was 8.72 ± 0.85 mm, with an implantation rate of 15.42% (3) against an implantation rate of 9.6% when estradiol was used only after the day of oocyte retrieval described by other center (4), both retrieving oocytes from unstimulated ovaries of PCOS women. The implantation rate described by Elizur et al. (1) in the HMG group (15.0%) was very close to that described using estradiol since the beginning of the cycle by Zhao (3), which suggests that both strategies similarly improve endometrial receptivity.
Wellington P. Martins Ph.D.
Carolina O. Nastri, M.D.
Rosana M. Reis, Ph.D.
Rui A. Ferriani, Ph.D.
Departamento de Ginecologia e Obstetrícia da Faculdade de Medicina de Ribeirão Preto
Universidade de São Paulo
Sao Paulo, Brazil
1. Elizur SE, Son WY, Yap R, Gidoni Y, Levin D, Demirtas E et al. Comparison of low-dose human menopausal gonadotropin and micronized 17beta-estradiol supplementation in in vitro maturation cycles with thin endometrial lining. Fertil Steril 2009;92:907-12.
2. Martins Wde P, dos Reis RM, Ferriani RA, de Araujo CH, Nastri CO, Filho FM. Endometrial preparation for in vitro oocyte maturation: early use of estrogen increases endometrial tissue and requires lower daily dosage: a cross over trial in ‘mock’ cycles. J Assist Reprod Genet 2006;23:241-6.
3. Zhao JZ, Zhou W, Zhang W, Ge HS, Huang XF, Lin JJ. In vitro maturation and fertilization of oocytes from unstimulated ovaries in infertile women with polycystic ovary syndrome. Fertil Steril 2009;91:2568-71.
4. Child TJ, Abdul-Jalil AK, Gulekli B, Tan SL. In vitro maturation and fertilization of oocytes from unstimulated normal ovaries, polycystic ovaries, and women with polycystic ovary syndrome. Fertil Steril 2001;76:936-42.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2009.10.051
The Authors Respond:
I wish to thank Martins et al. for their interest in our manuscript and their important letter to the editor. In their study (1) they compared two protocols of estradiol supplementation in polycystic ovary syndrome (PCOS) women undergoing in vitro maturation (IVM) cycles. Patients who received estradiol beginning on the first day of the menstrual flow achieved an endometrial thickness > 8 mm. However, other important cycle characteristics, such as the number of retrieved oocytes, maturation rate, the number of in vivo matured oocytes and pregnancy rates are not mentioned in that study. We have shown (2) that low-dose human menopausal gonadotropin (hMG) supplementation protocol is equivalent to estradiol protocol in terms of endometrial response but is superior to it in terms of the number of in vivo matured oocytes and the maturation rate 24 hours after oocyte retrieval.
These two variables were previously shown (3) to significantly improve embryo quality and pregnancy rates in IVM cycles. Therefore, we believe that when comparing two protocols designated to improve endometrial lining in IVM cycles, one must evaluate the impact on all variables contributing to success in IVM cycles and not only endometrial receptivity. By doing so, we will be able to improve pregnancy and delivery rates in IVM treatments.
Shai E Elizur, M.D.
Chaim Sheba Medical Center
Tel Hashomer, Israel
1. Martins Wde P, dos Reis RM, Ferriani RA, de Araujo CH, Nastri CO, Filho FM. Endometrial preparation for in vitro oocyte maturation: early use of estrogen increases endometrial tissue and requires lower daily dosage: a cross over trial in ‘mock’ cycles. J Assist Reprod Genet 2006;23:241-6.
2. Elizur SE, Son WY, Yap R, Gidoni Y, Levin D, Demirtas E et al. Comparison of low-dose human menopausal gonadotropin and micronized 17beta-estradiol supplementation in in vitro maturation cycles with thin endometrial lining. Fertil Steril 2009;92:907-12.
3. Son WY, Chung J, Demirtas E, Holzer H, Buckett WM, Chian RC, et al. Comparison of cycles programmed for IVM with and without in vivo matured oocytes retrieved. Reprod Biomed Online 2008;17(1):59-67
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2009.10.052