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Long oestradiol replacement in an oocyte donation programme

Jose Remohi1, Antonio Gutierrez2, Fidel Cano3,Amparo Ruiz1, Carlos Simon1 and Antonio Pellicer4
'instituto Valenciano de Infertilidad and Department of Pediatrics,Obstetrics and Gynecology, Valencia University School of Medicine, Valencia, Spain, Postdoctoral Fellow, on leave from Hospital Aranda de la Parra, Leon Guanajuato, Mexico,3Postdoctoral Fellow on leave from Department of Obstetrics and Gynaecology, Instituto de Ciencias de la Salud School of Medicine,Medellin, Colombia
4To whom correspondence should be addressed at: InstitutoValenciano de Infertilidad, Guardia Civil 23, 46020 Valencia, Spain

The objective of this study was to optimize, in terms of endometrial receptivity (embryo implantation), the limits of unopposed administration of oestrogens beyond 35 days
in an in-vitro fertilization (IVF) and ovum donation programme.Oocytes donated by 182 women undergoing IVF were distributed among 186 women treated by ovum donation. Five groups of recipients were established according to the duration of oestradiol valerate administration,in a 'prolonged follicular phase' protocol, before embryo replacement, employing oestradiol valerate at increasing doses up to 6 mg/day. Gonadotrophin-releasing hormone analogues (GnRHa) were simultaneously administered in ovulatory patients. The dosage of oestradiol valerate was maintained until oocytes were available for insemination
and subsequent transfer. Donors and recipients were equally distributed among groups in terms of age and cause of infertility. There was no difference among groups in serum oestradiol concentration the day in which progesterone was added to obtain a secretory transformation of the endometrium. An analysis of the ovum donation cycles showed no difference among groups in pregnancy and implantation rates after the replacement of a similar number of embryos. Successful implantation was observed even after 100 days of unopposed oestradiol valerate administration.Break-through bleeding increasingly appeared
according to the duration of oestrogen replacement. These clinical observations provide evidence that the concept of prolonged follicular phase' oestrogen replacement for
ovum donation can be maintained, at least as long as 15 weeks. However, because of the high (>44%) incidence of break-through bleeding after 9 weeks, it is advisable to stop
oestrogen treatment at this point. This protocol enormously facilitates the chances of synchronization between donor and recipient in an anonymous oocyte donation programme.

Key words: hormonal replacement/oestradiol valerate/ovum donation/pregnancy

Introduction

Oocyte donation was first created for women with ovarian failure. Nowadays, it is also an important option for infertile patients with ovarian function, such as low responders or women with genetic disorders (Remohi et al., 1993). However,the main problem of this technique is synchronization between donor and recipient, since the number of donors is limited and the number of days on which embryo transfer can be performed is also short due to the protocols of steroid replacement employed. In an attempt to resolve these problems, Navot et al. (1989) analysed several protocols of hormonal manipulation of the
endometrium; they described a 'long follicular phase protocol',consisting of the administration of oestrogens for 3-5 weeks before progesterone administration, finding no apparent adverse effect on endometrial morphology using this regimen for 35
days. Later reports have confirmed this (Younis et al., 1991).Clinical trials performing embryo transfers also support this concept. Serhal and Craft (1987) maintained recipients on oestrogens for 2—4 weeks before starting progesterone. Navot et al. (1991) demonstrated that even after 35 days of unopposed oestrogen administration, endometrial receptivity was
adequate. Using the long follicular phase protocol, they described a 48.5% pregnancy rate (Navot et al., 1991). Nevertheless, according to our knowledge, the unopposed administration of oestrogens has not yet been extended beyond these
limits.The aim of our study has been to optimize, in terms of endometrial receptivity and recipient availability, the limits of unopposed oestrogens as well as the appearance of breakthrough bleeding. For this purpose, the proliferative phase of our patients on the waiting list for ovum donation was prolonged until a donor became available.