In view of these variations, the theoretical probability of changing clinical management is 15% to 28% after the same evaluator reviews a slide37 and 22% to 39% after another observer evaluates the same slide.38
Refresher training fails to improve accuracy. To increase the accuracy and interobserver reproducibility of endometrial dating, Duggan and colleagues39 offered refresher training in histologic criteria after initial endometrial dating. However, they found no improvement in accuracy or inter-observer reproducibility after this training.
Timing of the endometrial biopsy also is important.40 Traditionally, endometrial biopsies have been performed a few days before the presumed onset of menstruation to reflect the maximal influence of progesterone on the endometrium. This practice recently has been questioned, with some researchers favoring biopsies performed in the midluteal phase.40,41
The method of determining the date of ovulation also varies considerably. Traditionally, next-menstrual-period dating is used, whereby the day of menses after the biopsy is labeled day 28 and presumed to have occurred 14 days after ovulation. The use of urine LH to determine the preovulatory LH surge and—15 days later—menstruation, has been suggested as a more precise method.42
Significant intercycle variation may occur within the same individual. Li and colleagues43 reported that within-subject, between-cycle variation of more than 2 days occurred in about 41% of patients.
Uncertain link to infertility. The link between an abnormal biopsy and infertility is questionable. Previous studies have documented abnormal endometrial biopsy results in the range of 31% to 35% in fertile women13,44 —rates almost comparable to those of women with infertility. Earlier investigators also demonstrated no significant differences in pregnancy rates between infertile couples with normal biopsy results, compared with those with abnormal findings.45
Before we consider it clinically significant, we require any LPD to be present in repeated cycles.
Clinical recommendations. Before we consider it clinically significant, we require any LPD to be present in repeated cycles, since approximately 20% to 80% of women with an abnormal biopsy have an “in-phase” endometrium on a repeat biopsy.13,46
The dating of endometrial biopsies should only be done by experienced histopathologists. We perform endometrial biopsies after cycle day 24, and confirm any out-of-phase abnormality in 2 consecutive biopsies. Further, before we diagnose the endometrium as “out of phase,” histologic dating must lag by at least 3 days.
In our practice, all endometrial biopsies are read by the senior author, who has had extensive experience with Noyes’ criteria for endometrial dating.
Is there a proven treatment?
Not surprisingly—given the disagreement about its incidence and diagnosis—LPD treatment also is controversial. Several case series, observational trials, and retrospective studies have explored whether treatment improves the chances of conception, but few randomized trials have taken up the issue.
Two main strategies have been suggested:
- Improving follicular dynamics using drugs such as clomiphene or gonadotropins, which not only produce a follicle but increase progesterone secretion during the luteal phase.
- Administering supplemental progesterone during the luteal phase and first trimester of pregnancy.
Clomiphene and other follicle-maturing drugs. Clomiphene increases FSH secretion and induces development of multiple or larger follicles. As a result, LH receptivity is enhanced. In addition, higher estrogen concentrations in the follicular phase increase steroid receptor content in the endometrium.
Although some studies support the use of clomiphene to treat LPD, in certain cases the drug may actually induce luteal phase defects in 30% to 50% of cycles.47 By its anti-estrogenic activity, clomiphene may suppress progesterone receptor levels, rendering the endometrium out of phase and less responsive to progesterone.
Supplemental progesterone use is supported by research from Lassey and colleagues,48 who demonstrated an association between LPD and abnormal expression of alpha-v-beta-3-integrin, the biomarker of uterine receptivity, which is likely responsible for the window of implantation. The endometrium of women with delayed maturation—that is, LPD—fails to express the alpha-v-beta-3-integrin when biopsied during the window of implantation (days 20 and 21). When given supplemental progesterone, the vast majority of these patients return to normal histologic status and alpha-v-beta-3-integrin expression.48,49
Progesterone versus clomiphene. Clinical trials have not established whether progesterone treatment is more effective than treatment with clomiphene or gonadotropin or no treatment. Problems with design and methodology in trials that do exist make it impossible to draw any firm conclusions from reports published thus far.
The literature includes numerous descriptive studies, most of which involved assessment of pregnancy rates before and after treatment.50 However, pregnancies that occur after therapy do not necessarily imply treatment benefit, but may reflect natural intercycle or biologic variation or spontaneous conception independent of treatment.
Randomized trials. Most of the studies published to date are case series and observational studies, which are subject to methodologic bias. To the best of our knowledge, only a few randomized studies of treatment efficacy have been published.51-53 All included only a few patients and lacked adequate power to detect any differences.50