1 Fukuda Ladies Clinic, 309 Kariya, Ako, Hyogo 678-0239, Japan and 2 Laboratory of Reproductive Biology, Juliane Marie Center for Children, Women and Reproduction, Rigshospitalet, Section 5712, University Hospital of Copenhagen, Blegdamsvej 9, DK-2100, Copenhagen, Denmark
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Abstract |
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Key words: age/contralateral versus ipsilateral ovulations/follicular phase length/pregnancy/right-sided versus left-sided ovulations
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Introduction |
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While the ovulation pattern in succeeding cycles has been the subject of a number of studies, no conclusive data are available on whether ovulations occur from alternating sides, (i.e. contralaterally) (Dukelow, 1977; Hodgen, 1982
; Marinho et al., 1982
; Gougeon and Lefevre, 1984
), from the same side (i.e. ipsilaterally) (Werlin et al., 1986
) or at random (Clark et al., 1978
; Check et al., 1991
). However, it has been observed that in cycles with a follicular phase length of <14 days ovulation tended to occur contralaterally, while in cycles with a longer follicular phase, ovulation tended to occur at random (Wallach et al., 1973
; Fukuda et al., 1996
). A significantly longer follicular phase of ipsilateral ovulations compared with contralateral ovulations was observed in infertile women (Potashnik et al., 1987
; Fukuda et al., 1996
, 1998
). These observations were based upon a group of infertile women. However, Ecochard and Gougeon, 2000 reported that the side of ovulation had no effect on cycle characteristics in a group of fertile women (199 cycles of 80 women) (Ecochard and Gougeon, 2000
). In the present study, we evaluated whether ovulation characteristics and pregnancy potential correlated with age, assessing early follicular phase concentrations of FSH, follicular phase length, pregnancy rate per cycle, right or left-sided ovulation and the ovulatory pattern of two consecutive cycles. Furthermore, we evaluated whether these parameters differed between women who did or did not conceive as a result of treatment with intrauterine insemination (IUI) or IVF.
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Materials and methods |
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Ovulation characteristics and pregnancy in infertile women
Observations were performed between June 1990 and December 1999. Follicular development and ovulatory pattern were assessed in a total of 1033 natural cycles of 258 women (mean age ± SD: 31.2 ± 4.7 years, range 2245) undergoing infertility treatment. The diagnosis of infertility was as follows: male factor, 205 couples; unknown, 53 couples. A total of 213 women underwent 727 IUI cycles and 92 women underwent 306 IVF cycles; 52 women underwent both IUI and IVF cycles. The mean number of cycles examined in each patient was four (range 110). All women showed natural menstrual cycles and did not receive any exogenous gonadotrophins or clomiphene citrate for ovarian stimulation. Follicular development was monitored daily by transvaginal ultrasound (SSA-250A scanner with a 5.0 MHz convex vaginal probe, Toshiba, Tokyo, Japan or Sonovista CS or EX scanner with a 5.0, 6.0 or 7.5 MHz mechanical sector vaginal probe, Mochida, Tokyo) from the time when the follicle measured 14 mm in diameter until formation of corpus luteum or oocyte retrieval.
Ovulation was predicted by the urinary LH surge (L-check: Nipro, Osaka or Gold Sign LH: Morinaga, Tokyo, Japan). Cycles with two or more pre-ovulatory follicles were excluded from this study. During each treatment cycle, the side at which the dominant follicle developed was determined. Day 1 was defined as the first day of the menstruation. The follicular phase length was defined as the day of follicle rupture or oocyte retrieval (e.g. if follicle rupture is confirmed on day 14, follicular phase length is 14 days). The follicular phase length was correlated with age, dividing into the following age groups: 29, 3034, 3539 and
40 years. Concentrations of FSH on cycle day 3 were also measured, using an automated chemiluminescence system. Intra-assay variance was within 5% and interassay variance was within 6%. All the 1033 cycles were assessed as to whether right (R)- or left (L)-sided ovulation occurred, and 870 cycles of 242 women were also assessed as to whether contralateral (C) or ipsilateral (I) ovulation occurred. Of these 1033 cycles, 113 pregnancies were obtained. The pregnancy rate per cycle was assessed in each age group. In addition, mean age, basal FSH, the frequency of right-sided ovulations (i.e. R/R+L) and contralateral ovulations (i.e. C/C+I) of pregnant women and non-pregnant women <39 years of age were assessed and compared. Part of the material from the present study has been used in the previous study (410 natural cycles of 123 infertile women) (Fukuda et al., 1996
) since the procedure protocol and the causes of infertility were unchanged throughout this study.
Ovulation characteristics in fertile women
Observations for this part of the study were performed between January 1997 and December 1999. Ovulation from the right or the left ovary was assessed using transvaginal ultrasound in 1057 cycles of 856 women (mean age ± SD: 36.2 ± 6.4 years, range 2050). The women had previously given birth to at least one live born infant and attended our clinic for assessment of uterine cancer, vaginal discharge and other conditions unrelated to infertility. In 712 cycles a dominant follicle of >14 mm diameter was located and in the remaining 345 cycles a distinct corpus luteum was identified. If a dominant follicle was observed during the first visit, the disappearance of the dominant follicle was confirmed at a second visit 714 days later. If a corpus luteum was observed at the first visit, the presence of menstruation was confirmed at a second visit ~14 days later. Ovulations were consecutively assessed and contralateral or ipsilateral ovulation was examined in a total of 233 natural cycles of 123 women. Of these 123 women, 18 (3847 years old) participated in this study as volunteers and were examined in up to 10 consecutive cycles. Information on the starting day and length of menstruation cycle was obtained from each woman and, unless ultrasound observations confirmed this information, data were not included. The follicular phase length in this group was not assessed.
Statistical analysis
Statistical evaluation was performed using Student's t-test, 2 test or Fisher's exact test. Stepwise regression analysis was performed between age and basal FSH, age and follicular phase length, and age and C/C+I ratio. Statistical analysis concerning the link between contralaterality and pregnancy rate adjusted more correctly for age was also performed before and after log transformation. Differences were considered significant at P < 0.05. Results are presented as mean ± SD.
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Results |
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Ovulation characteristics with ageing in fertile and infertile women
Ovulations from the right and left ovary were presented according to age in 2090 natural cycles (Table II). Observations in the fertile as well as the infertile group were included. At almost all ages from 2050 years, ovulation from the right ovary occurred more often than from the left, showing a similar pattern in fertile and infertile women, though at some ages ovulation occurred more often from the left ovary than the right. The frequency of ovulations from the right at age <29 years showed a relatively high ratio of ~58%. This ratio was reduced to 54% in the age groups 3034 and 3539 years, while women >40 years showed a ratio of 56%. The overall average frequency was 55% (1156/2090), which was significantly higher than 50% (P = 0.001).
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Ovulation characteristics and achievement of pregnancy correlated with age in infertile women
The pregnancy rate per cycle was 14% (48/336) in the age group <29 years, 12% (50/401) in the 3034 group, 5% (14/267) in the 3539 group and 3% (1/29) in women >40 years. The pregnancy rate of the four groups correlated with follicular phase length and inversely correlated with basal FSH. The ratio of right-sided ovulations remained almost constant despite a slight decrease from 3039, while the ratio of contralateral ovulations decreased with age. The statistical analysis of the C/C+I ratio versus the pregnancy rate adjusted more correctly for age yielded a highly statistically significant correlation (before log transformation, P < 0.0087, r = 0.60; after log transformation, P < 0.02, r = 0.54). Thus, the ratio of contralateral ovulations (C/C+I) showed a clear correlation with the pregnancy rate, whereas that of right-sided ovulations (R/R+L) was unrelated to the pregnancy rate, as shown in Figure 1.
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Discussion |
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The average follicular phase length correlated inversely with age and decreased ~2.5 days from the youngest to the oldest age group. The follicular phase length is similar between ovulations occurring from either the right or the left ovary. In contrast, the follicular phase length of ovulations taking place in the ovary opposite to the previous cycle (i.e. contralateral ovulation) was shorter than that of ipsilateral ovulation, a difference which decreases with age.
The present study explains and extends a number of previous studies, which include a smaller study group with a more restricted age range (Dukelow, 1977; Clark et al., 1978
; Hodgen, 1982
; Marinho et al., 1982
; Gougeon and Lefevre, 1984
; Check et al., 1991
; Ecochard and Gougeon, 2000
).
The present study was unable to detect any difference in ovulation characteristics between fertile and infertile women. However, the majority of cases in the infertile group was classified as male factor, with only a small fraction being classified as unknown factor, thereby excluding women with tubal factor (hydrosalpinx), chocolate cyst or ovulation disorder (polycystic ovaries). Therefore, some women of the infertile group may not be infertile themselves per se, and the design of this study does not allow for a thorough analysis of whether fertile and infertile women show similar age-related ovulation characteristics. However, based on the present results no major differences seem to be obvious. It might be interesting to compare the ovulation characteristics between infertile women with male factor and those with tubal factor or chocolate cyst, or fertile women and infertile women with tubal factor or chocolate cyst.
Ecochard and Gougeon, 2000 reported no difference in follicular phase length of fertile women when comparing contralateral and ipsilateral ovulations, being 14.59 days (Ecochard and Gougeon, 2000). This follicular phase length corresponds to that observed in the middle age group (i.e. 3039 years) of the present study and correlated well with the reported mean age of women of 32.3 years. The present study demonstrates that the difference of the follicular phase length between contralateral and ipsilateral ovulations decreases with age, becoming almost undetectable in women >40 years. In addition, Ecochard and Gougeon reported a frequency of contralateral ovulation of 51.3%, which compares favourably with that of the present study observed in the 3539 year age group (Ecochard and Gougeon, 2000
).
It is not known why the younger age group of <29 years shows the highest percentage of contralateral ovulation and also the highest rate of right-sided ovulation. This may show that the interovarian control mechanism is well maintained in younger women. Further studies are obviously needed to clarify the underlying mechanism.
We have previously demonstrated that contralateral ovulation favours pregnancy more than ipsilateral ovulation in natural cycles (Fukuda et al., 1996, 1999
, 2000a
) and clomiphene citrate-stimulated cycles (Fukuda et al., 1998
, 1999
, 2000a
). Moreover, we have recently demonstrated that right-sided ovulation also favours pregnancy more than left-sided ovulation in natural cycles of both fertile and infertile women (Fukuda et al., 2000b
). In the present study the pregnancy rate per cycle decreased with age from 14 to 3%. The ratio of right-sided ovulations remained constant, whereas the ratio of contralateral ovulations decreased with age from 62 to 42%. The ratio of contralateral ovulations correlated with pregnancy potential and ovarian age. This finding may also indicate that the mechanism of the pregnancy-favouring effect of contralateral ovulation is different from that of right-sided ovulation; the underlying mechanism of the former may originate from the ovary itself (i.e. follicle/oocyte quality), enhancing pre-embryo development, and that of the latter may originate outside the ovary (i.e. asymmetry of ovarian vascularization), enhancing implantation by increased output of oestradiol and/or testosterone from the corpus luteum on the right ovary.
A steady decline in the frequency of contralateral ovulations is observed in the present study. At the age of 3738 years the frequency is 50%, an age when an abrupt decline in number of small antral follicles and primordial follicles is seen (Faddy et al., 1987, 1992
; Gosden et al., 1989
; Gosden and Faddy, 1994
; Gougeon et al., 1994
; Faddy and Gosden, 1995
; Gougeon, 1996
; Broekmans et al., 1998
; Scheffer et al., 1999
). Therefore, it may be speculated that the ratio of contralateral ovulations is affected by these factors. However, it is not known how the ratio of contralateral ovulations can be affected by the pool of primordial follicles or the number of small antral follicles. There are a number of parameters or markers for ovarian reserve or ovarian age such as basal concentrations of FSH, high concentrations of oestradiol, low concentrations of inhibin-B and shortened follicular phase. In accordance with this, the present study shows a reduced follicular phase length and increased basal FSH concentrations as women get older. The pregnancy rate per cycle decreased with age in parallel to a reduced ratio of C/C+I, contrasting the R/R+I ratio which remained almost constant. In addition, infertile women becoming pregnant as a result of treatment expressed a higher ratio of C/C+I, longer follicular phase, lower basal FSH concentrations and younger age than the group that did not conceive. Also, in the pregnant and non-pregnant group, no difference in the ratio of R/R+L could be detected. Thus the ratio of C/C + I might be used as a new parameter expressing the ovarian reserve or ovarian age.
In conclusion, human ovulation exhibits age-related characteristics with regard to the frequency with which ovulation occurs from the same or alternating ovaries. The frequency with which ovulation occurs from the right ovary (~55% of all the ovulations) is independent of age. The pregnancy rate per cycle decreases with age from 14 to 3% and correlates with the ratio of C/C+I. It might be speculated that in younger women the interovarian control mechanism is well maintained, while such a mechanism is impaired in older women.
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Acknowledgements |
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Notes |
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References |
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Submitted on April 17, 2001; accepted on September 14, 2001.