Human Reproduction, Vol. 14, No. 3, 787-792,
March 1999
© 1999 European Society of Human Reproduction and Embryology
Endometrial pinopodes indicate a shift in the window of receptivity in IVF cycles
1 Department Obstetrics and Gynaecology, Imperial College School of Science, Technology and Medicine, Hammersmith Hospital, DuCane Road, London W12 ONN, UK, 2 The Jones Institute for Reproductive Medicine, Department of Obstetrics and Gynaecology, Eastern Virginia Medical School, Norfolk, Virginia 23507-1627 USA
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Abstract |
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The formation of endometrial pinopodes detected by scanning electron microscopy may be a specific marker for uterine receptivity. Aiming to assess the effects of ovarian stimulation on pinopode formation, we examined sequential endometrial biopsies from 17 oocyte donors. Seven normally menstruating women served as controls. Up to four samples were taken from each woman at 24–72 h intervals between days 14 and 24, giving a total of 69 samples. The day of oocyte retrieval was designated day 14 in ovarian stimulation cycles and the day of luteinizing hormone surge was designated day 13 in natural cycles. Endometrial morphology and pinopode numbers were similar in both groups. Fully developed pinopodes appeared in only one sample per cycle, indicating their short life span. However, the cycle day these structures appeared varied up to 5 days between women and the distribution was as follows: day 18 (n=2), day 19 (n=7), day 20 (n=4), day 21 (n=3), day 22 (n=1) in ovarian stimulation cycles, and day 20 (n=2), day 21 (n=2), day 22 (n=3) in natural cycles. Furthermore, accelerated pinopode formation in ovarian stimulation cycles was positively correlated with day 13 progesterone. Our findings show that ovarian stimulation does not affect endometrial pinopode formation in terms of quantity and life span. The cycle days when pinopodes form are specific to the individual, being on average 1–2 days earlier in ovarian stimulation than in natural cycles. These changes in pinopode expression may reflect shifts in the window of receptivity, resulting in ovo-endometrial asynchrony and limiting implantation success in in-vitro fertilization.
Key words: endometrial pinopodes/implantation/IVF/nidation window/uterine receptivity
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Introduction |
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Implantation failure is a major factor limiting the success of in-vitro fertilization (IVF). On average, up to 90% of apparently healthy zygotes transferred in utero are destined to vanish, giving no signs of trophoblastic attachment and production of human chorionic gonadotrophin (HCG). The initiation of implantation requires a blastocyst to interact with an endometrium that has gained receptivity. While the importance of embryo quality has been clearly demonstrated (Liu et al., 1988
), a further cause for the reduced implantation rates may be an impairment of endometrial receptivity, due to high concentrations of sex steroids resulting from ovarian stimulation used for IVF. This suggestion is supported by higher implantation rates in hormonal replacement treatment (HRT) cycles after ovum donation than the standard IVF cycles (Paulson et al., 1990; Edwards et al., 1991). Receptivity is a concept introduced by Psychoyos (Psychoyos, 1976, 1986) and has been shown to last only for several hours in rodents, determining a narrow nidation window. Relative knowledge in our species is limited due to the obvious experimental draw-backs and the lack of specific criteria to define a receptive endometrium.
An interesting approach to this enigma appears to be morphological studies using scanning electron microscopy (SEM). At the time of implantation, the apical membranes of the epithelial cells lining the uterine cavity lose their microvilli and develop large and smooth membrane projections (Psychoyos and Mandon, 1971a). Due to their pinocytotic function, these projections were named pinopodes (Enders and Nelson, 1973). Their development is progesterone dependent, and in rodents coincides strictly with the implantation window (Psychoyos and Mandon, 1971b; Martel et al., 1991). In the human endometrium similar structures were observed around the 20th day of a normal cycle (Martel et al., 1981), which is the presumed day of blastocyst attachment. Hormonal treatments have been shown to advance or retard the timing of pinopode formation. During ovarian stimulation with clomiphene citrate followed by human menopausal gonadotrophin (HMG)/HCG pinopodes form earlier, on days 17 or 18 (Martel et al., 1987). In contrast, under HRT pinopodes form later, around day 22 (Psychoyos and Nikas, 1994). Yet these days represent only mean values deriving from a group of patients. When sequential (every 2–3 days) midluteal samples were taken from natural or HRT cycles, the timing of pinopode appearance was found to vary up to 5 days between women. Sequential sampling also revealed that pinopode formation follows a distinct pattern allowing us to distinguish between developing, fully developed or regressing pinopodes. Fully developed pinopodes were always confined to one sample, showing a life span of less than 48 h. Finally the number of pinopodes was different between patients and there was a strong correlation between pinopode numbers and implantation after embryo transfer (Nikas et al., 1995, 1996, 1997; Nikas and Psychoyos, 1997).
Little information on pinopodes is available in ovarian stimulation cycles induced by gonadotrophins only. Conventional histology has shown advanced endometrial maturation in HMG/HCG cycles (Garcia et al., 1984). Theoretically, reduced implantation rates in IVF cycles could result from impaired or premature endometrial maturation, which could be accompanied by alterations in pinopode expression. Indeed, in a recent study pinopodes were found to form as early as 4 days after HCG administration (Kolb et al., 1997). However, this study dealt more with the overall changes of surface morphology than with pinopode expression.
The aim of the present work was to assess the temporal expression of pinopodes as a specific marker for receptivity in IVF cycles induced by gonadotrophins. In addition, serum concentrations of steroid hormones were assessed during the preovulatory period and correlated with pinopode findings.
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Materials and methods |
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Patients and ovarian stimulation
Seventeen donors undergoing ovarian stimulation at the Jones Institute for Reproductive Medicine were studied. Requirements for admission to the Donor Egg Program included: (i) age 21–35 years, (ii) cycle day 3 endocrine values [oestradiol, follicle stimulating hormone (FSH), luteinizing hormone (LH)] within normal limits, (iii) a normal uterine cavity by hysterosalpingogram. The stimulation protocol used was similar to that previously described (Toner et al., 1991
). In general, leuprolide acetate 1.0 mg s.c. daily (TAP Pharmaceuticals, Deerfield, IL, USA) was begun in the mid-luteal phase (days 21–23) of the preceding menstrual cycle. Follicular stimulation with HMG and FSH (Pergonal and Metrodin, respectively; Serono Labs, Randolph, MA, USA), was initiated on day 3 of the menstrual cycle and continued until administration of HCG.
Seven women with regular menstrual periods and proven fertility served as controls. The age distribution of these women was similar to that of the donor group (29.3 ± 2.6 versus 29.8 ± 3.4 respectively). The dates in controls were assigned by detection of the LH surge using a commercially available urine kit (OvuQuick, Quidel, San Diego, CA, USA), and validated by dates of onset of the next menstrual period and histological dating according to morphological criteria (Noyes et al., 1950). All patients gave written, informed consent prior to the study, which had been approved by the Institutional Review Board of Eastern Virginia Medical School.
Endometrial tissue collection and preparation
Fifty-one endometrial samples were obtained sequentially from 17 donors. Samples were taken every 48–72 h, on days 14–24 (see Table I). Day of oocyte aspiration was designated day 14 of the cycle. In the natural cycle group 18 samples were taken on days 17–23 (see Table II). Sampling of uterine fundus was performed using a Pipelle (Unimar Inc., Wilton, CT, USA). The endometrial tissue was fixed in 2.5% (w/v) glutaraldehyde solution in a sodium cacodylate buffer (0.1 mol/l pH 7.3). The specimens were dehydrated in an acetone series, dried in a critical point drier using carbon dioxide, mounted on the specimen holder, coated with gold, and examined under a Stereoscan 360 SEM (Cambridge Instruments, Cambridge, UK). Many tissue pieces were viewed from each biopsy to increase the likelihood that the observations were representative, since the endometrium may show more advanced or retarded morphology from one area to another.
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Hormone assays and statistics
Blood samples were drawn on the day of HCG and the day after, corresponding to days 12 and 13 of the cycle. Serum oestradiol concentrations were measured using a microparticle enzyme immunoassay (IMx Estradiol, Abbott Laboratories, Abbott Park, IL, USA). The sensitivity of the assay was 25 pg/ml, and the intra- and inter-assay coefficients of variation were 3.8–10.4% and 4.3–16.0% respectively. Serum progesterone concentrations were measured using a radioimmunoassay (Pantex direct 125I Progesterone, Santa Monica, CA, USA). The assay was sensitive at a threshold level of 0.2 pg/ml. Intra- and inter-assay coefficients of variation were 2.9–10.9% and 7.3–7.9% respectively. Hormone concentrations were related to the temporal expression and number of pinopodes using the Spearman rank order correlation and the Mann–Whitney U tests where appropriate. Statistical significance was set at the 0.05 level.
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Results |
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The surface morphology of secretory epithelial cells showed a characteristic pattern of evolution similar to that described in natural and HRT cycles (Martel et al., 1981
; Nikas et al., 1995). After ovulation the central area of the cell surface starts to bulge and the microvilli are mainly distributed in this area. As the cycle proceeds, bulging involves the entire cell surface and the distribution of microvilli becomes even. Smooth apical projections, usually smaller than pinopodes, are occasionally seen in small groups in the endometrial folds. Around day 17 of a normalized cycle the microvilli reach their maximum development, being long, thick and upright. By day 18, bulging increases and the tips of microvilli may appear swollen. On day 19 bulging is pronounced, the microvilli decrease in number and length and fuse. Smooth and slender membrane projections form, arising from the entire cell apex (developing pinopodes). On days 20, microvilli are virtually absent and the membranes protrude and fold maximally, with shapes resembling mushrooms or flowers (fully developed pinopodes). On day 21 bulging decreases slightly and small tips of microvilli reappear on the membranes, which are now wrinkled and cell size starts to increase (regressing pinopodes). By day 22 pinopodes and cell bulging have largely regressed. Days 23 and 24 are characterized by a further increase in cell size, decrease in bulging and cells become dome-shaped and covered with short and stubby microvilli.
This sequence of changes was observed in all cycles studied. However, the cycle days when these changes occurred varied greatly between women, and some women showed accelerated and others retarded maturation (Figures 1, 2 and 3). Thus fully developed pinopodes appeared within a range of 5 days in ovarian stimulation cycles as follows: day 18 (n=2), day 19 (n=7), day 20 (n=4), day 21 (n=3), day 22 (n=1). In the majority of cycles (9 of 17), maturation was advanced with pinopodes already formed by day 19. In natural cycles fully developed pinopodes covered a three day range as follows: day 20 (n=2), day 21 (n=2), day 22 (n=3). Expression of fully developed pinopodes in ovarian stimulation cycles was significantly accelerated for an average of 1–2 days in comparison to natural cycles (19.6 ± 1.1; median 19 and 21.1 ± 0.9; median 21, respectively; Mann–Whitney U test: z = –2.604, P = 0.009). The number of pinopodes present was scored in three grades: abundant, moderate, and few, depending on the percentage of the endometrial surface occupied by pinopodes (>50%, 20–50% and <20% respectively). These grades did not show any statistically significant difference between the two groups. Tables I and II
summarize these findings.
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Serum oestradiol and progesterone concentrations on days 12 and 13 of the cycle varied considerably between donors (Table III
). No correlation was found between day 12 or 13 oestradiol concentrations or day 12 progesterone concentrations and the timing of appearance or the number of pinopodes (data not shown). Similarly, this was true for patients' age, numbers of gonadotrophin ampoules administered or eggs retrieved (Table III). However, we observed a statistically significant correlation between day 13 progesterone concentrations and timing of fully developed pinopodes (Spearman's r = –0.7070; P = 0.002), as well as a significant difference in mean progesterone concentrations between donors with and without fully developed pinopodes by day 19 (Table III).
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Discussion |
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Our findings show that ovarian stimulation produces a pattern of surface endometrial maturation which is similar to that seen in natural or HRT cycles (Martel et al., 1981
, 1987; Psychoyos and Nikas, 1994; Nikas et al., 1995). The life span of fully developed pinopodes never exceeded 48 h, suggesting that these structures represent a transient cell state. Furthermore, pinopode numbers in ovarian stimulation cycles were similar to those noticed in other cycles, showing that high hormonal concentrations do not inhibit pinopode expression. Interestingly, high hormonal concentrations did not seem to blunt individual differences on the timing of pinopode appearance, which covered a range of 5 days. However, the average day of pinopode formation was 1–2 days earlier in ovarian stimulation, as compared to natural cycles studied in the present and in previous work (Martel et al., 1981, 1987; Psychoyos and Nikas, 1994). In natural cycles, we may assume that there is an inherent synchrony between the maturing uterus and the developing embryo, ensuring that both partners will meet at the right stage. It is therefore reasonable to postulate that reduced implantation in IVF cycles is due to an ovo-endometrial asynchrony. In IVF, embryonic development is probably delayed while the uterus is advanced, resulting in an early closure of the nidation window, before the zygote eventually reaches a stage capable of initiating implantation. An additional cause of implantation failure can be the disparity in maturation between the stroma and the epithelium observed in histology (Toner et al., 1993). Since a paracrine communication between epithelium and stroma may be important at the beginning of implantation, this disparity could compromise uterine receptivity or early trophoblastic invasion.
Ovarian stimulation using gonadotrophins alone appears more physiological than using a combination of clomiphene citrate and gonadotrophins, since in the latter the surface morphology was greatly advanced, with pinopodes already regressed by day 20, in 85% of cycles studied (Martel et al., 1987). This is in agreement with the fact that ovarian stimulation using gonadotrophins only leads to higher pregnancy rates (Tummon et al., 1992). However, our findings seem to differ somewhat from those of Kolb et al. (1997), who observed pinopodes as soon as 4 days after HCG. In our material the earliest pinopode formation occurred 6 days after HCG. This discrepancy may be due to differences of the stimulation protocol used, or these investigators might have possibly included as pinopodes small apical projections which appear occasionally at the uterine folds during early luteal phase. Furthermore, their study protocol did not allow them to biopsy their patients sequentially, or even after day 19 (HCG+7), which might have obscured the progressive changes in pinopode expression.
In our study group the pinopodes occurred on days 18–22, thus covering a 5 day interval. The expression of other proposed markers of receptivity, e.g. certain integrin subunits, was found to occur also during a 5 day interval (Lessey et al., 1994). Yet sequential sampling in our study revealed that in each woman fully developed pinopodes were present for less than 2 days. Whether sequential sampling could elaborate a similarly limited individual expression for other markers of uterine receptivity as well, remains an open question.
A further finding in our study included the link between elevated preovulatory progesterone concentrations and early appearance of pinopodes. The impact that early progesterone rise bears on success of IVF remains a matter of continuing dispute. An explanation for this controversy could lie in the diversity of consequences associated with this phenomenon. Early luteinization possibly results in better quality zygotes (Legro et al., 1993). Moreover, prolonged exposure to progesterone may decrease uterine contractility at the time of embryo transfer, which might be another parameter likely to affect the outcome of an IVF cycle (Fanchin et al., 1998). On the other hand, in a study of endometrial histology Chetkowski et al. (1997) have shown premature progesterone rise to induce early secretory transformation. Furthermore, pinopode findings in the present study could imply that early progesterone rise (the threshold of which remains yet to be defined) may accelerate closure of the window of receptivity and thus compromise the chances of successful implantation.
Regarding some concerns about the reliability of microscopic findings after sequential sampling, SEM is a suitable method to address this question. SEM can view the entire surface of the specimen and very often the sites of a previous sampling are visible as gaps surrounded by regenerating epithelium. Such areas tend to localize at the edge of the biopsy pieces and the rest of the tissue looks perfectly normal, in terms of epithelial integrity and evolution, including pinopode formation (Figure 4). Therefore, sequential endometrial sampling provides reliable material for SEM studies.
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To conclude, our study on sequential endometrial samples shows that ovarian stimulation does not alter endometrial pinopode formation as regards their quantity and short life span. The cycle days when pinopodes form greatly vary between women and on average, they occur 1–2 days earlier in ovarian stimulation than in natural cycles. It is possible that these temporal aberrations in pinopode expression may relate to shifts in the window of receptivity, resulting in ovo-endometrial asynchrony and hence in suboptimal implantation rates in IVF.
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Notes |
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3 To whom correspondence should be addressed
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