1 Department of Reproductive Science and Medicine, Imperial College Faculty of Medicine, St Mary's Hospital, Paddington, London W2 1PG and 2 Reproductive Medicine Laboratory, Department of Reproductive and Developmental Sciences, University of Edinburgh, 37 Chalmers St, Edinburgh EH3 9WE, UK
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Abstract |
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Key words: luteal phase/menstrual cycles/ovulation/polycystic ovaries/progesterone
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Introduction |
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The significance of PCO, in terms of fertility, in the population of asymptomatic women is unknown, but it seems reasonable to postulate that such women have a significant number of anovulatory cycles despite reporting regular menses. PCO were found to be present in >50% of ovulatory women presenting with infertility who had a primary diagnosis of tubal, male factor or unexplained infertility (Kousta et al., 1999). This was twice the expected prevalence and implies an effect of PCO on the fertility of these women.
The aim of this study was to investigate the frequency of ovulation in a group of women with PCO who presented with infertility, but who reported regular cycles and to assess the pattern of luteal phase progesterone secretion in these women.
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Materials and methods |
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Progesterone analysis
Luteal phase progesterone excretion was assessed by analysis of urinary ratios of pregnanediol:creatinine in early morning urine samples collected on consecutive days commencing on day 10 of the cycle and proceeding to the first day of menses. Samples were collected in three consecutive cycles and stored at 20°C. Samples from completed cycles were delivered frozen to the laboratory where they were centrifuged and aliquoted for assay of pregnanediol-3-glucuronide (P-3-G) for 10 min at 1000 rpm, as previously described (Yong et al., 1992)
Analysis of data
Differences in cycle length between the groups was determined by the MannWhitney U-test. Progesterone metabolite results are expressed as P-3-G:creatinine ratios. Patterns of luteal phase P-3-G were normalized to the first day of the subsequent menstrual period for statistical analysis. Analysis of luteal phase P-3-G patterns was initially made by calculating mean area under curve (AUC) for each patient, with the baseline taken as the mean of the first (day13) and last (day 0) result in each case. Differences between groups were then determined by analysis of variance followed by Tukey/Kramer post hoc test. Differences in day 10 and peak P-3-G:creatinine were analysed by the MannWhitney U-test. Throughout, significance was assumed when P < 0.05.
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Results |
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Abnormal patterns of P-3-G:creatinine were seen in a number of patients, usually characterized by sudden falls or swings in excretion. Qualitative analysis of individual cycles revealed that there were 4/30 cycles in the PCO and 12 /30 in the infertile normal group that showed a grossly abnormal pattern. Two of these cycles came from one patient in the PCO group and nine from three patients in the infertile normal group. A typical example of a single cycle from each group is shown in Figure 2.
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That the early luteal phase values show the most difference is emphasised when comparing the mean data for the early (days 13 to 7 inclusive) or late (days 6 to 0) luteal phase between groups, as shown in Figure 4. There were no significant differences between the groups in the late luteal phase, but both infertile groups had lower values than the fertile women in the early luteal phase; normal fertile versus PCO or infertile normal, P < 0.002. These differences remained significant even if the data from one patient in the PCO group and the three in the infertile normal group who had been found to have very abnormal progesterone profiles were omitted (P < 0.04).
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Discussion |
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Interestingly, the increased variability in cycle length in both of the infertile groups was due in part to a high prevalence of short cycles, 16% being of <25 days duration. No cycles of this length were documented in the women of proven fertility. Short cycles have been reported in several of the studies investigating cycle length in the general population, but the majority of these were found in perimenopausal women (Treloar et al., 1967; Sherman and Korenman, 1975
). A gradual decrease in cycle length of 23 days was observed between the ages of 20 and 40 years with an increase in the number of short cycles from the age of 40 years to the time of menopause. The short cycles found in two groups in our study could not be attributed to differences in age because the age was similar in the three groups and perimenopausal women were excluded. A later study of >2000 menstruating women of all ages reported that 24% had cycles of
25 days, data which are similar to those presented here (Wood et al., 1979
). The significant proportion of women with short and long cycles in this group led the investigators to conclude that normal cycle length should be considered to be between 21 and 35 days. Applying these criteria to our data we concluded that only three cycles (one in each group) could be considered abnormal in length.
There was a narrow range of subject-to-subject variation in total urinary P-3-G:creatine ratio across the luteal phase in fertile women. This range was increased in the PCO group and was wider still in the infertile women with normal ovaries. Analysis of individual cycles revealed that a few patients were responsible for the majority of these abnormal cycles. Three patients in the infertile normal group failed to produce a normal P-3-G profile in any of the three cycles studied. The reason for the apparent fluctuation in P-3-G during the luteal phase in these patients is not clear, but is unlikely to be a methodological problem as there were no similar examples in the normal fertile group. There was no apparent link between cycle length and the profile of the P-3-G:creatine ratio.
The higher P-3-G concentrations in the fertile women were most apparent in the first half of the luteal phase. Similar data were found in two previous studies, one investigating serum progesterone levels in women presenting with infertility (Lenton et al., 1978) and a second comparing levels in cycles in which conception occurred with those from non-conception cycles (Lenton et al., 1982
). In the first study, progesterone levels were found to be lower specifically in the first half of the luteal phase in infertile women who were judged to be ovulatory compared with a control group of women who were of proven fertility. Although it was assumed that the deficiency of progesterone was implicated in the infertility of these women, increasing plasma progesterone levels by a variety of medical interventions had no impact on fertility. The ovarian morphology of these groups was not investigated, but in our study similar results were obtained in women with infertility regardless of ovarian morphology.
The main factor distinguishing the cycles of women with PCO from those of the infertile women with normal ovaries, was the peak level of P-3-G:creatinine reached during the mid-luteal phase. Although levels in both infertile groups were lower initially, P-3-G in the women with PCO eventually rose to be similar to those seen in the fertile women. However, this peak was reached 1 day later. In the second study (Lenton et al., 1982), progesterone levels in conception cycles were clearly higher than in non-conception cycles as early as day 38 after the LH surge (equivalent to our day 12 to 6). This was presumably too early to be a result of corpus luteum rescue due to conception. A total of 1520% of values in the non-conception group were low. The lower mean early luteal and peak levels in the infertile groups in the current study are a reflection of the number of cycles in which progesterone levels were variable throughout the luteal phase. This may be due to abnormal follicular development in these patients, resulting in inadequate corpus luteum function.
Poor follicular development was suggested to be the cause of infertility in another study in which steroid levels were assessed throughout the menstrual cycle in women with previously unexplained infertility (Dodson et al., 1975). As with our data, close examination of individual cycles revealed that a minority of the group was responsible for most of the abnormal cycles. Poor progesterone secretion followed significantly lower levels of pre-ovulatory estradiol in these patients.
Although the most aberrant P-3-G secretion profiles were seen in the infertile women with normal ovaries, there was no apparent correlation between cycle length and luteal phase P-3-G values. This suggests that in this study at least, an abnormal cycle length was not a good predictor of poor corpus luteum function.
In summary, we have found that women with PCO who report regular cycles do not have more variation in cycle length than women with normal ovaries. There was, however, a greater degree of variability in luteal-phase progesterone production, but this was also evident in infertile women with normal ovaries. The most apparent difference between fertile and infertile women, regardless of ovarian morphology, was the level of progesterone metabolite in the early luteal phase. In both infertile groups the lower levels were mainly due to a few patients who appeared to have consistently abnormal progesterone secretion which may be implicated in their infertility. However it is likely that, in most patients, other factors are also involved. That ovulatory PCO may associated with sub-fertility, is demonstrated by a recent study to determine the prevalence of PCO in regularly-cycling women with infertility of various causes (Kousta et al., 1999). Interestingly, this morphology was over-represented in women with tubal disease, sperm dysfunction and unexplained infertility compared with a control group of parous volunteers. The implication of this association is not clear, but our study suggests, that in the majority of patients, impaired fertility in ovulatory women with PCO is not primarily due to inadequate progesterone production.
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Notes |
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References |
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Submitted on June 16, 2001; accepted on January 15, 2002.