1 Unidad de Medicina Reproductiva, Clínica Las Nieves, Santiago and 2 Unidad de Medicina Reproductiva, Clínica Las Condes, Santiago, Chile.
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Abstract |
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Key words: corpus luteum/ectopic/implantation
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Introduction |
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Published data have shown that the increasing concentration of HCG during pregnancy is not followed by a proportional increment in ovarian steroid production. This finding suggests that following the rescue of the corpus luteum, ovarian steroidogenesis is not controlled by HCG alone (Norman et al., 1988; Kratzer and Taylor 1990
; Johnson et al., 1993a
). Recent studies have shown lower concentrations of oestradiol and progesterone in ectopic pregnancies when compared to normal intrauterine pregnancies (Norman et al., 1988
; Johnson et al., 1993b
; Lower et al., 1993
). However, it has been demonstrated that trophoblastic tissue produced HCG with equal immuno- and bioactivity when implanted either in the Fallopian tube, as occurs in ectopic pregnancy, or in the uterine cavity, (Kratzer and Taylor, 1990
). The rescue of the corpus luteum should then be unaffected by the site of implantation. However, the comparison of normal intrauterine pregnancies and failed intrauterine pregnancies (anembryonic pregnancies) have also shown different steroid production. This suggests that an impaired CL function could be the result of a failure in trophoblastic division (Norman et al., 1988
; Johnson et al., 1993c
). To date, most of the information published provides hormonal values for isolated samples, in late stages of pregnancy and once the trophoblastic tissue has failed to produce normal amounts of HCG.
The objective of this report was to provide information on CL production of progesterone and oestradiol in the first week of pregnancy and its relation to embryo quality.
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Materials and methods |
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All patients were under luteal support with injectable (i.m.) progesterone (Laboratorie Chile S.A., Santiago, Chile) 50 mg in oil per day from the day of transvaginal aspiration.
Patients were divided in three groups as follows: Group 1 (n = 11) pregnancies ended in a single normal live birth; Group 2 (n = 10) pregnancies ended in a spontaneous clinical abortion and Group 3 (n = 7) were ectopic pregnancies.
Doubling times (DT) for HCG were calculated using the following formula: DT = log 2x(time interval in days)/log (HCG2 at end of DT/HCG1 at beginning of DT) (Pittaway et al., 1985). Delayed DT was defined as an average HCG doubling time
1.8 days, in the following time intervals days: 1215, 1518 and 1821, or one absolute value of DT above 2 days in any of the three intervals.
The absolute values of plasma ß-HCG and oestradiol, in the three groups, were compared using one-way analysis of variance and Student's t-test. The level of significance was P < 0.05.
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Results |
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Absolute data for HCG, oestradiol and progesterone are shown in Table I.
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Progesterone production was not significantly disminished in both ectopic pregnancies and abortions. Analysis of ectopic pregnancies with normal and delayed DT, showed a trend for reduced progesterone production in delayed DT patients (Figure 2). In the abortion group there was no difference in progesterone secretion between normal and delayed patients.
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Discussion |
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Ectopic pregnancies with normal developing embryos and normal HCG production modulate a normal response of the CL, measured by the levels of oestradiol and progesterone. The site of implantation did not seem to affect this response. On the other hand, oestradiol levels were significantly diminished in ectopic pregnancies with delayed DT for HCG secretion. These data suggest that in ectopic pregnancies, two different populations can be differentiated. One population presents with normal DT HCG and normal steroid production, suggesting that the trophoblast and embryo are normal and had the potential to continue if they were properly implanted. The main limitation here seems to be related to anatomical limitations at the site of implantation. The other population of ectopic pregnancies, with delayed DT for HCG and low steroid levels, would have been aborted, regardless of whether it were implanted in the Fallopian tube or the uterine cavity.
Although the presence of multiple CL may affect the bioavailability of HCG, it is almost impossible to correct data by the number of CL. However all the patients have multiple follicles and CL after ovarian stimulation so the comparison between them would be valid.
It has been reported that lower steroid concentrations seen in ectopic pregnancies, despite apparently normal HCG values, suggest that the hormone acts in the ovary through intermediate substances produced by the endometrium (Liu et al., 1991). Further support in this direction has been published by Lower et al. who suggested that a metabolic or biochemical signal is triggered as a result of direct contact of the trophoblast with the endometrium (Lower et al., 1993
). The results of this study do not support the theory that uterine implantation is a prerequisite for normal CL rescue. HCG duplication rate, and not its absolute value, seems to be a better sign of normal development and this is the main factor in maintaining CL function. The data in the current study demonstrated that ectopic pregnancies with normal DT behave like normal pregnancies in terms of oestradiol and progesterone secretion.
Oestradiol levels were apparantly lower in abortions, as compared with normal intrauterine and ectopic pregnancies, regardless of the DT of HCG but the differences were not significant. Nevertheless, this suggests that intrauterine abortions may constitute a more homogeneous population in which all the embryos implanted will fail to continue growing, in spite of having normal DT early in gestation, although for a limited period of time (Lenton et al., 1982). It is postulated that if the sampling is extended beyond day +21, most of these abortions will exhibit a delayed DT for HCG.
These data suggest that the trophoblast of intrauterine pregnancies that will end in abortion is not able to produce normal amounts of oestradiol regardless of whether or not it has enough HCG support. No genetic analysis was performed on these miscarriages that could explain, at least partially, the impaired trophoblast. Data was reported (Liu et al., 1991), that also showed that in 56.5% of spontaneous abortions with normal DT for HCG a drop in oestradiol concentrations was observed on day +15 after embryo transfer, suggesting that steroidogenesis in the CL is a better predictor of trophoblastic growth, and its impairment would end in a miscarriage. It should be noted that the lack of statistical significance in our data may have been due to the small number of cases examined.
Luteal dynamics can be affected by progesterone support in IVF luteal phases. Thus, progesterone may not represent an ideal indicator of luteal function. A more specific indicator could be relaxin which is produced mainly by the corpus luteum. A previous study (Emmi et al., 1991) demonstrated that pregnant patients with oocyte donation due to ovarian failure had no detectable levels of relaxin. However, the same authors conclude that this hormone is not necessary for pregnancy maintenance. Based on this observation, the significance of change on relaxin plasma levels between normal and ectopic pregnancies and abortions will need further investigation.
No associations have been found between other CL proteins, such as the pregnancy-associated plasma protein-A (PAPP-A) or Schwangerschaft protein-1 (SP-1) (Johnson et al., 1993b). However this can be explained by the relative lack of sensitivity of the assays more than the actual usefulness of the markers.
Progesterone levels are not significantly reduced in ectopic pregnancies and abortions as compared to normal pregnancies. This may be due to the supra-physiological exogenous support of the luteal phase with progesterone in oil. This exogenous support produces high levels of plasma progesterone, so subtle variations in endogenous production cannot be easily detected. However, progesterone levels are of relative value, an earlier study (Azuma et al., 1993) has shown that 2.3% (8/345) of pregnancies that resulted in normal birth had serum progesterone values below the fifth percentile of single IVF pregnancies at week 4 of gestation. Oestradiol values were also below the fifth percentile, but thereafter they rose to values just within normal limits. Evaluation of the minimal concentration of progesterone to maintain ongoing human pregnancy has not been established.
Finally, it has been reported that luteal oestradiol is not necessary in the establishment of a clinical pregnancy in the human and it was also demonstrated that embryos start to produce oestradiol as early as 18 days after embryo transfer (Zegers-Hochschild and Altieri, 1995). It is therefore likely that oestradiol and progesterone are indirect markers of CL recognition of a normal embryo rather than hormones responsible for the maintenance of pregnancy by themselves. It has been shown (Johnson et al., 1993b
) that progesterone and oestradiol in normal pregnancies were derived from the CL but in ectopic pregnancies the CL failed and the main origin of these hormones was the trophoblast as early as week five of pregnancy.
The data presented here suggest that an ultrasonography with no intrauterine gestational sac between the 4th and 5th week of pregnancy, and normal oestradiol levels with normal rising of HCG represents a high risk of having an ectopic pregnancy. On the other hand, if HCG and oestradiol levels are decreasing a more expectant type of management would be acceptable.
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Notes |
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References |
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Submitted on November 24, 1998; accepted on June 14, 1999.