Department of Obstetrics and Gynecology, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan
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Abstract |
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Key words: hysteroscopy/mid-secretory endometrium/miscarriage
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Introduction |
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The aims of the present study using hysteroscopic assessment of the mid-secretory phase endometrium were: (i) to explore whether or not there is a relationship between hysteroscopic findings and early phase pregnancy outcome after implantation; and (ii) to compare endoscopic findings with histological and endocrinological backgrounds.
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Materials and methods |
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These pregnant patients were analysed retrospectively with special reference to a possible relationship between endoscopic findings and pregnancy outcome. Nine patients, whose pregnancies ended in ectopic pregnancy or in miscarriage suspected to be due to significant factors, e.g. submucosal leiomyomata, uterine anomalies and anti-phospholipid antibody syndrome, were excluded from the study. Three patients were lost to follow-up after conception. Thus, 160 women were included in this analysis.
Hysteroscopy and classification of findings
Hysteroscopy was scheduled in a menstrual cycle not manipulated with any hormonal agents. Patients were well informed regarding the procedure and were asked to prevent conception in the cycle. All patients ovulated and the procedure was carried out on days 79 after ovulation; basal body temperature (BBT) was monitored and/or the collapse of developing follicles documented by transvaginal ultrasound. The procedure was usually carried out without anaesthesia, but occasionally a paracervical block (PCB) of 10 ml 1% lidocaine was necessary. Lidocaine is not thought to have vaso-constrictive or dilative effects. No apparent change was observed in vasculature between pre- and post-PCB in those patients receiving PCB in the middle of hysteroscopy. Patients received cleansing and disinfection of their vulva and vagina in the dorsal lithotomy position. A rigid hysteroscope which had a 4.5 mm outer diameter and gave a foreoblique vision of 30° with the optical axis (Model A3726, Olympus, Tokyo, Japan) was inserted into the uterus transcervically and the uterine cavity was cleaned and expanded by irrigation with 5% glucose solution. After introducing the hysteroscope through the internal uterine os, the uterine cavity was scanned thoroughly. After completion of the examination, endometrial biopsy was performed in 32 patients who agreed to the procedure.
Hysteroscopic findings were observed and diagnosed by more than three gynaecologists, including the authors (H.M. and K.K.) using videotape recordings. Endoscopic assessments of the mid-secretory endometrium on days 79 after ovulation were classified according to the appearance of both the glandular openings and the blood vessels on the endometrial surface as either `good' when ring-type glandular openings and well-developed vascular networks were visualized over almost the whole endometrium (Figure 1a,b,c), or `poor' when dot- and/or punctate-type glandular openings and fine vasculature were predominantly observed (Figure 2a,b,c
; Sakumoto et al., 1992
).
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Hormone assay
Serum progesterone and oestradiol, taken on the day of hysteroscopy, were measured in 83 patients by enzyme immunoassay kits (DPC Estradiol and Progesterone assay kits; Diagnostic Products Corporation. CA, USA). The normal values for progesterone and oestradiol in the luteal phase (days 315 after ovulation) were 0.231.6 ng/ml (SI conversion factor = 3.18) and 0.0090.230 ng/ml (SI conversion factor = 3.671) respectively.
Ultrasonographic diagnostic criteria of blighted ovum and embryonic death
In this study, early pregnancy loss (early spontaneous abortion) was categorized into blighted ovum or intrauterine embryonic death, based on the findings of serial transvaginal ultrasonography. Blighted ovum was designated in cases where embryonic echoes were never visualized in the gestational sac, and embryonic death in cases where embryo heart action, which had been once identified, disappeared within 11 weeks of gestation (menstrual age).
Statistical analyses
Analysis of variance (ANOVA) and 2 or Fisher's exact tests were used to assess the differences for clinical items, and histological and hormonal findings between the `good' and `poor' groups. P < 0.05 was considered to be statistically significant.
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Results |
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Histological and hormonal backgrounds of hysteroscopic appearance
Endometrial specimens from 32 patients were examined to specify the post-ovulatory day of the cycle according to histological criteria for dating the endometrium (Table III). In 20 patients in the `poor' group, `in-phase' endometrium was diagnosed in 13 (65.0%), and `out-of-phase' endometrium was diagnosed in seven (35.0%). In the `good' group, `in-phase' endometrium was documented in all 12 patients examined. Thus, histological findings were significantly different between the two groups (P = 0.0204). In the tissue sections taken from the `good'-appearing endomerium, the distended tortuous glands with intra-luminal wisps of secretion, which were lined by low columnar to cuboidal epithelial cells, opened widely through a protruded brim, making a ring-type appearance on the endometrial surface (Figure 1d,e
). On the other hand, in those from the `poor'-appearing sites of the endometrium, the tortuous glands, which were lined by columnar epithelial cells containing intracellular vacuoles, opened with relatively narrow openings, giving rise to a spot- or punctate-like appearance on the endometrial surface (Figure 2d,e
).
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Discussion |
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First, of the 160 patients studied, 98 (61.3%) had been categorized as `poor'. This was close to the 45.9% found in a previous study (Sakumoto et al., 1992) which dealt with infertile patients. The considerably high percentage of `poor' endometrium seems to be due to the fact that the overwhelming majority of patients were infertile and/or with a history of early abortion, although the percentage of `poor' appearance is unknown in the fertile female population. Secondly, the frequency of patients with a history of early spontaneous abortion was significantly higher in the `poor' group than in the `good' group. This suggests that unfavourable hysteroscopic findings are associated with early pregnancy loss after implantation. Thirdly, there were no significant differences between the two groups for any of the assisted interventions of index pregnancies. Therefore, it seems to be valid to analyse the outcome of pregnancies in association with hysteroscopic findings of the two groups. Thus, the incidence of early spontaneous abortion was significantly higher in the `poor' group than in the `good' group. The incidence of 14.5% in the `good' group was similar to the abortion rate in the general population of women. It is also noteworthy that the incidence of intrauterine embryo death in early spontaneous abortion appeared to be relatively higher in the `poor' group (51.5%) than in the `good' group (33.3%), although the difference was not statistically significant. In the `poor' group, poor conditioning of the endometrium might be more important than chromosomal abnormality as a cause of early pregnancy loss. The high prevalence of chromosomal abnormality in abortions occurring at or before 8 weeks (Kajii et al., 1980
) suggests that the majority of blighted ova could result from lethal chromosomal abnormalities. On the other hand, the low abortion rate after ultrasound-proved viability of embryo/fetus in early pregnancy (Simpson et al., 1987
; Rosen et al., 1990
) appears to suggest that the majority of embryo deaths might result not from chromosomal abnormalities but from poor conditioning of the endometrium. Thus, the mid-secretory endometrium diagnosed to be endoscopically `poor' in appearance might not be well prepared for early development of the implanted ovum.
Luteal phase defect is defined as a lag of >2 days in histological maturation of the secretory endometrium compared with day of the cycle. This delayed maturation, which cannot allow for the timely opening of the temporal window for implantation of the fertilized ovum (Formigli et al., 1988; Bergh and Navot, 1992
), is often a direct result of decreased hormone secretion by the corpus luteum, though the underlying causes may be multiple. One of the controversies concerning the histological diagnosis of lutal phase defect has revolved around issues of technique and timing of the endometrial biopsy (Li et al., 1989
; Castelbaum et al., 1994
). In the present study, where hysteroscopy-oriented biopsies were performed, `out-of-phase' secretory endometrium was observed in 35.0% of the `poor' group, but in none of the `good' group, although the size of samples examined was small. In other words, more than one-third of the endometrial samples with unfavourable hysteroscopic findings demonstrated delayed histological maturation compared with day of the cycle. This suggests that hysteroscopic appearance of the secretory endometrium may reflect the histological endometrial maturation status. It has been noted by several authors (Vanrell and Balasch, 1986
; Tulppala et al., 1991
; Peters et al., 1992
) that the incidence of luteal phase defect may be higher in patients with a history of recurrent abortion. Thus, it is again conceivable that the mid-secretory endometrium with unfavourable hysteroscopic appearance might be inadequately conditioned for early development of the implanted ovum. There have been a number of morphological, immunohistochemical and molecularbiological observations on cyclical changes of the endometrial glands and stroma. In particular, immunohistochemical profiles of oestrogen and progesterone receptors, tumour-associated glycoprotein 72, placental protein 14, and carbohydrate in glandular epithelial cells have been demonstrated to be associated with secretory differentiation of glandular function (Waites et al., 1988
; Ravn et al., 1992
; Osteen et al., 1992
). Comparative studies between hysteroscopic appearance and these observations of the endometrium should be performed in the near future.
Hormonal data in luteal phase defect have been in some dispute to date. Low FSH concentrations and low FSH:LH ratios in the follicular phase, low serum concentrations of progesterone and oestrogen in the luteal phase, and decreased response of the endometrium to progesterone have been implicated (Soules et al., 1989). In clinical practice, attention has been directed to measurement of serum progesterone concentrations for diagnosing luteal phase defects (Cumming et al., 1985
). Most important, however, is the impressive evidence documenting the lack of a relationship between serum progesterone concentrations and endometrial histology. This is also the case in our study which examined a possible correlation between serum progesterone concentrations and hysteroscopic findings. Furthermore, no significant association was observed between luteal progesterone:oestradiol ratios and hysteroscopic appearance in the present study, although it has been reported that, after ovulation induction, a high luteal progesterone:oestradiol ratio is associated with ongoing pregnancies and a lower progesterone:oestradiol ratio is seen in cycles leading to spontaneous abortion (Maclin et al., 1990
).
In conclusion, our data suggest that the hysteroscopic appearance of the mid-secretory endometrium is a better prognostic factor for pregnancy outcome than any hormonal data investigated at this stage of the menstrual cycle.
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Acknowledgments |
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Notes |
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References |
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Submitted on March 7, 2000; accepted on July 5, 2000.