1 Unidad de Medicina Reproductiva, Clínica Las Condes, Santiago, 2 Laboratorios Silesia, Santiago, Chile, 3 Unidad de Fertilidad del Country, Bogota, Colombia and 4 FERTILITY Centro de Fertilización Asistida, Sao Paulo, Brazil
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Abstract |
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Key words: IVF/oocyte donation/progesterone supplementation/vaginal ring
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Introduction |
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In recent years, a polysyloxane vaginal ring with an external diameter of 60 mm and a cross-section of 9 mm was developed with the aim of delivering natural progesterone continuously (Jackanicz, 1983). This delivery system, which proved to be effective as a contraceptive for lactating women (Massai et al.,1999
), was later re-formulated and used as luteal supplementation for women participating in (IVFembryo transfer), and as the only source of progesterone in functionally agonadal women participating in oocyte donation. This vaginal ring contains 1 g of natural progesterone and its in-vitro release is 10 mg/day. When placed in the vagina, it provides continuous release of progesterone for as long as 90 days. In a previous study (Zegers-Hochschild et al., 1996
), progesterone concentration in peripheral circulation and endometrial histology was studied in eight women with premature ovarian failure, during a cycle prior to oocyte donation. The vaginal ring was inserted after the endometrium had proliferated with a daily dose of oral oestradiol-17ß (4 mg per day). While endogenous progesterone was <1 nmol/l before vaginal ring insertion, the mean ± SE of plasma progesterone measured 24 h after was 20.7 ± 2.1 and fell to 15.7 ± 0.3 nmol/l 18 days later (Figure 1
).
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The objective of this study was to evaluate the efficacy in the establishment and maintenance of pregnancy of this vaginal ring when compared with daily i.m. injections of progesterone in women treated with IVFembryo transfer and oocyte donation.
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Materials and methods |
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IVFembryo transfer trial
A total of 505 patients participated in this study. All patients were subjected to ovarian stimulation, which included daily s.c. injections of leuprolide acetate starting in the luteal phase of the previous cycle, or after discontinuing oral contraceptives. The time of exposure to the agonist prior to ovarian stimulation varied between patients, depending on clinical judgement and the need to coordinate dates of follicular aspiration. Follicular recruitment and maturation was induced with variable doses of human menopausal gonadotrophin (HMG), starting on the second or third day of menstruation and maintained until at least three follicles were 16 mm in diameter. Daily doses were established according to clinical judgement, based on the number of follicles, their size and plasma oestradiol. Follicular aspiration was performed 36 h after exposure to 10 000 IU of human chorionic gonadotrophin (HCG). Embryos were transferred to the uterine cavity 48-72 h after follicular aspiration. On the day of oocyte retrieval, patients were randomly allocated to either i.m. progesterone (50 mg/day) or a vaginal ring containing 1 g of progesterone. Plasma HCG was measured 12 days after embryo transfer. If pregnancy was documented the vaginal ring (Laboratorio Silesia S.A., Santiago, Chile) was left in situ for 5 more weeks. Patients allocated to i.m. progesterone continued daily injections for the same length of time. Transvaginal ultrasounds were performed 3 and 5 weeks after embryo transfer. A clinical pregnancy was diagnosed after sonographic visualization of an intrauterine gestational sac. Multiple gestation was diagnosed when two or more gestational sacs were visualized 5 weeks after embryo transfer.
Oocyte donation trial
A total of 153 patients with either premature ovarian failure or repeated failure to respond to ovarian stimulation were subjected to HRT for oocyte donation. Endometrial proliferation was induced with a fixed oral dose of micronized oestradiol-17ß, (4 to 6 mg/day). On the day of follicular aspiration in the oocyte donors, recipients were allocated either to i.m. progesterone, 100 mg/day (n = 70) or to a vaginal ring containing 1 g of natural progesterone (n = 83). Oral concentration of oestradiol was maintained at a fixed dose throughout the treatment period. If pregnancy was documented (12 days after embryo transfer), the vaginal ring was replaced by a new ring containing 2 g of progesterone which was left in the vagina for 7 weeks.
After proper consent, fresh oocytes were donated by women under 35 years of age who were simultaneously participating in an IVFembryo transfer programme. Consent forms were also signed by oocyte recipients.
For both trials, comparisons were performed on the clinical pregnancy and live birth delivery rates after embryo transfer and implantation rates (number of gestational sacs/ number of embryos transferred) according to the age of the female partner. Statistical analysis used 2 and Fisher tests.
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Results |
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Overall results are provided in Table V. The clinical pregnancy rate was not significantly higher in women using vaginal ring over i.m. progesterone, (39.8 and 28.6% respectively). However, the implantation rate was significantly higher in patients using vaginal ring, 19.9% compared to 11.6% for i.m. progesterone (P = 0.006). When donors achieved a pregnancy, implantation rate in their simultaneous recipients was 29.9% (23/77) in vaginal ring compared to 19.7% (12/61) in i.m. progesterone. This difference did not reach statistical significance, probably due to the small number of embryos transferred in each group (23 pairs of patients). Similarly to the IVFembryo transfer trial, multiple pregnancy rates were as high in vaginal ring users as in i.m. progesterone (42.4 and 41.1% respectively).
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Discussion |
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It has been well established that when progesterone is released from the vagina, the concentration reached in endometrial tissue is far greater than when the hormone is administered i.m. (Miles et al., 1994). In women treated with oocyte donation, exogenous progesterone is the only source of the hormone. When using the ring, its concentration in peripheral circulation (10-20 nmol/l) is much lower than the concentration reached after 100 mg of i.m. progesterone (>80 nmol/l) or progesterone concentration of 30-40 nmol/l found in the mid luteal phase of spontaneous conception cycles (Zegers-Hochschild, 1988
). When the vaginal route is used to deliver progesterone, measurement of circulatory concentrations is therefore quite meaningless. This study supports the concept of a `first uterine pass effect' (Fanchin et al., 1997
). Furthermore, this study demonstrates that when progesterone is delivered in the vagina, circulatory concentrations do not have to mimic the hormonal concentration found in normal ovulatory cycles. In fact, much less is required to achieve endometrial maturation. The mechanisms by which progesterone released in the vagina reaches the uterine cavity in higher concentrations than peripheral circulation has been thoroughly reviewed (Cicinelli and de Ziegler, 1999
). Progesterone concentration measured in the uterine vein in three women undergoing hysterectomy was three to seven times higher than peripheral circulation after 24-36h of exposure to the vaginal ring containing 1g. The ratio of progesterone in uterine vein/antecubital vein was 67.1/22.6, 90.5/12.4 and 65.0/9.5 nmol/l. In two other cases where surgery was indicated because of large fibroids in the isthmus region and occupying part of the vagina, progesterone concentrations in the uterine and antecubital veins were not different (32.2/27.5 and 10.9/10.6 nmol/l).
In oocyte recipients, once pregnancy was documented; the ring containing 1 g was replaced with a new ring containing 2 g of progesterone. This decision was made after some initial cases (not included in this report) experienced uterine bleeding coinciding with pregnancy. Based exclusively on empirical grounds it was decided to increase progesterone concentration in the ring once conception was documented in oocyte recipients. None of these pregnant patients exposed to the ring containing 2 g had uterine bleeding during their gestation.
Although the overall efficacy of the vaginal ring in IVFembryo transfer is not superior to the i.m. route, women prefer the ring as it avoids the discomfort of daily punctures and skin lesions derived from repeated injections. Moreover, in comparison with the use of micronized progesterone in tablets and progesterone gel, which have to be inserted in the vagina at least twice daily, the ring is placed in the vagina only once during the whole treatment period. Preliminary data of an acceptability trial conducted in 27 women that had used vaginal ring and i.m. progesterone in two different cycles demonstrated that, provided both treatments were understood by the patient as having the same efficacy, the majority of women would prefer vaginal ring to daily injections if exposed to a new treatment cycle.
Concerning endometrial bleeding in IVF patients, when the first value and doubling time of HCG was normal, the presence of vaginal spotting did not seem to interfere with the outcome of pregnancy. Some doctors, when exposed to vaginal spotting in the presence of positive HCG, increased progesterone either by adding i.m. progesterone, or changing to a ring containing 2 g of progesterone. Others just waited until spotting stopped. In many cases where progesterone was added, vaginal bleeding ceased, but this also happened without extra medication. Furthermore, since HCG was only measured from day 12 after embryo transfer, the number of biochemical pregnancies and their outcome is unknown. It will not be possible from this study to elucidate how to treat these cases or whether other forms or doses of hormonal supplementation are required to avoid bleeding.
The mechanism of uterine bleeding in IVF patients using the ring is not well understood. Bleeding does not take place when oestradiol or the oestradiol/progesterone ratio is maintained constant, as in oocyte donation cycles, except in very few cases when the ring containing 1 g was maintained after day 12 of embryo transfer. In these cases, increasing vaginal progesterone immediately stopped bleeding. Perhaps occasional bleedings associated with IVF are related to oscillations in endogenous oestradiol or in the local ratio between oestradiol and progesterone rather than progesterone concentration alone. On the other hand it has been well documented that in women without functional ovaries, after the endometrium has proliferated and progesterone is added, histological dating in the luteal phase is not affected by the presence or absence of oestradiol (De Ziegler et al., 1992). Furthermore, evidence is also available which suggests that luteal oestradiol is not required for the establishment and maintenance of pregnancy in women treated with oocyte donation (Zegers-Hochschild and Altieri, 1995
). Perhaps, in the presence of an active ovary as in IVF, the luteal rise in endogenous oestradiol needs to be compensated with extra progesterone.
New studies will be required to understand the mechanism by which uterine bleeding takes place in some women undergoing ovarian stimulation supplemented with progesterone via vaginal ring.
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Acknowledgments |
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Notes |
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References |
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Submitted on April 18, 2000; accepted on July 10, 2000.