1 Fukuda Ladies Clinic, Ako, Japan and 2 Laboratory of Reproductive Biology, Juliane Marie Center for Children, Women and Reproduction, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark
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Abstract |
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Key words: fertile women/infertile women/left-sided ovulation/pregnancy/right-sided ovulation
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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 yet available on whether ovulation occurs 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 <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 ovulation was observed compared with contralateral ovulation (Potashnik et al., 1987
; Fukuda et al., 1996
). In addition, it has previously been shown that the pregnancy potential of oocytes from contralateral ovulation is increased compared with those from ipsilateral ovulation (Fukuda et al., 1996
, 1998
, 1999
). However, it is unknown whether the fertility potential of oocytes from the right and left ovaries also differs. In this study, these questions were approached using a relatively large population comprising two separate groups of fertile and infertile women, the latter group undergoing treatment with intrauterine insemination (IUI) or in-vitro fertilization (IVF). In addition, the follicular phase length, treatment outcome and, on a subset of cases, hormone profiles of follicular fluid and serum at the mid-luteal phase in infertile women undergoing IVF or IUI were also evaluated with respect to right- and left-sided ovulation.
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Materials and methods |
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Side of ovulation and follicular phase length in infertile women
Observations were performed between June 1990 and December 1999. The follicular development and ovulation were assessed in a total of 1033 natural cycles of 258 women (age 31.2 ± 4.7 years, mean ± SD, range 2245) undergoing infertility treatment. The causes of infertility were as follows: male factor, 205 couples; unknown, 53 couples. Two hundred and eighteen 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 4.0 (range 110). None of the women received exogenous gonadotrophins or clomiphene citrate for ovarian stimulation. Follicular development was monitored daily by transvaginal ultrasound [SSA-250A Toshiba scanner (Tokyo, Japan) with a 5.0 MHz convex vaginal probe or Sonovista CS or EX Mochida scanner (Tokyo, Japan) with a 5.0, 6.0 or 7.5 MHz mechanical sector vaginal probe] 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 luteinizing hormone surge (L-check®; Nipro, Osaka, Japan or Gold Sign LH®; Morinaga, Tokyo, Japan). Cycles in which two or more pre-ovulatory follicles developed were excluded from this study. During each 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 was confirmed on day 14, follicular phase length was 14 days).
IVF procedure in infertile women
Of the 92 women undergoing IVF treatment using natural cycles, the causes of infertility were as follows: male factor, n = 72; unknown, n = 20. The mean number of cycles examined in each patient was 3.3 (range 18). In at least one previous IVF attempt pre-embryo development was obtained for all these couples. All procedures were performed as described previously (Foulot et al., 1989). In brief, human chorionic gonadotrophin (HCG) was given when the dominant follicle measured >18 mm in diameter and the oocyte was retrieved 3435 h after HCG injection using transvaginal ultrasound-guided follicle puncture. The oocyte retrieval rate, fertilization rate, cleavage rate, rate of pre-embryo formation/total number of oocytes retrieved, pregnancy rate/cycle and implantation rate (clinical pregnancies/pre-embryos replaced) were assessed in right-sided and left-sided ovulation cycles. Clinical pregnancy was confirmed by the presence of a gestational sac with transvaginal ultrasound.
Measurement of steroid hormones in follicular fluid obtained at oocyte retrieval and in serum obtained at mid-luteal phase from infertile women
In order to assess the health status of the dominant follicle, hormone profiles of follicular fluid obtained at oocyte retrieval were monitored as described previously (Yding Andersen, 1993, 1995
; Fukuda et al., 1995
). A subset of follicular fluid samples were selected at random ensuring that samples from the right-sided and the left-sided ovulation cycles were equally represented. The concentrations of oestradiol, progesterone, testosterone and androstenedione were measured, and the ratios of oestradiol/testosterone, oestradiol/androstenedione and oestradiol/testosterone + androstenedione in right-sided and left-sided ovulation calculated. Moreover, serum at the mid-luteal phase (+7 day, 7 days after oocyte retrieval or follicle rupture) was collected from a subset of infertile women who showed at least both one right-sided and one left-sided ovulation, and steroid hormone concentrations were measured using automated chemiluminescence system (ACS) for oestradiol, progesterone and testosterone and radioimmunoassay for androstenedione. Follicular fluid and mid-luteal samples did not originate in the same subset of women. Intra-assay variance was
5% and interassay variance was
6%. Part of the material from the present study was 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.
Side of ovulation and pregnancies from right-sided and left-sided ovulation in fertile women
Observations for this part of the study were performed between January 1997 and December 1999. The side of ovulation was assessed using transvaginal ultrasound in 1057 non-pregnant cycles of 856 women (age: 36.2 ± 6.4 years, range 2050). These women who had given birth to at least one live-born infant previously attended our clinic for assessment of uterine cancer, vaginal discharge and other conditions unrelated to fertility problems. In 712 cycles a dominant follicle of >14 mm in diameter was located and in the remaining 345 cycles a distinct corpus luteum was identified in either the right or the left ovary. 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. Information on the starting day and length of menstruation cycle was obtained from each woman. Unless the ultrasound observations confirmed this information, the data were excluded.
The number of pregnancies from the right-sided and the left-sided ovulation was assessed in 569 pregnant cycles of 533 women (age: 28.3 ± 3.1 years, range 2046, 36 women became pregnant twice) who attended our clinic for confirmation and assessment of pregnancy after having conceived naturally. At 59 weeks of gestation the position of the corpus luteum was identified in either the right or the left ovary, simultaneously with confirmation of a gestational sac in utero. These 533 women were different from the 856 fertile women described above.
Statistical analysis
Statistical evaluation was performed using Student's t-test, 2 test or Fisher's exact test. The odds ratio and 95% confidence intervals (CI) were used when pregnancy rates were compared. Differences were considered significant at P < 0.05. Results are presented as mean ± SD.
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Results |
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From the assessment of a total of 569 cycles where the woman was pregnant, the dominant follicle developed in the right ovary in 361 cases. The 361 pregnancies resulted in 229 live-born infants, 21 spontaneous abortions and 111 artificial abortions. The remaining 208 pregnant cycles were confined to the development of the dominant follicle in the left ovary. The 208 pregnancies resulted in 130 live-born infants, six spontaneous abortions and 72 artificial abortions. Those women showing spontaneous or artificial abortions had given birth to at least one live-born infant previously. The ratio of pregnancies from right-sided ovulation per total number of pregnancies was 63.4% (361/569), similar to that of infertile women (64.6%), and was significantly higher than the ratio of right-sided ovulation per total number of non-pregnant cycles (54.7%, 578/1057) [odds ratio 1.44 (95% CI 1.281.62), P = 0.0006] as shown in Table IV.
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Discussion |
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The largest previous study included a total of 572 natural cycles and found a frequency of right-sided ovulation of 54.5% (Check et al., 1991), which is nearly identical to that which we found (54.8%). This study included only infertile women, whereas our study included both fertile and infertile. However, we were unable to demonstrate any difference between the fertile and infertile groups. An asynchrony between the activity of the two ovaries is not unique to humans. A number of other species exhibits differences in the activity of the two ovaries, some even more pronounced than in humans. In birds only the left ovary is active whereas the right ovary remains quiescent, a pattern also seen in whales and chinchillas. If the left ovary in birds is removed or becomes functionally impaired the right ovary will develop into an active gonad. A predominance of ovulation from the right ovary has also been observed in the cow, although the anatomy is known to differ from that of humans (Nation et al., 1999
). The mechanism by which the two ovaries differ in their activity is to our knowledge unknown for other species as indeed for humans.
Assuming that the two ovaries experience an equal endocrine control of pituitary hormones, it is interesting to note that the concentration of oestradiol and testosterone in serum from the mid-luteal phase 7 days after ovulation or oocyte retrieval is higher when ovulation occurs on the right ovary compared with the left. This may suggest that the mechanism that promotes establishment of pregnancies from oocytes deriving from the right ovary is related to anatomical asymmetries. The vascularization may be different and the development of other organs such as the kidneys and the adrenal glands may be of importance. To evaluate whether the vascularization is different we are presently performing colour Doppler ultrasound measurements. However, this does not exclude the possibility that oocytes deriving from the right ovary, for some unknown reason, possess an intrinsically enhanced pregnancy potential causing the observed effects.
The ratio of pregnancies from right-sided ovulation per total number of pregnancies was remarkably similar for each group of patients: IVF, 62.5%; IUI, 65.1%; fertile women, 63.4%, thereby suggesting that the mechanism is unrelated to the overall fertility potential of the women. It has previously been demonstrated that contralateral ovulation in succeeding cycles enhances pregnancy in natural cycles (Fukuda et al., 1996, 1999
, 2000
) and in clomiphene citrate stimulated cycles (Fukuda et al., 1998
, 1999
, 2000
). If the dominant follicle develops in the ovary opposite to where ovulation took place in the previous cycle, the follicular fluid contains a more favourable androgen to oestrogen ratio and the oocyte is more prone to undergo fertilization and pre-embryo development in vitro compared to that of two successive ovulation cycles from one ovary. However, pre-embryo development in right-sided ovulation is lower than in left-sided, thereby suggesting that the mechanism which increases the fertility potential of oocytes from the right ovary is different from that of contralateral ovulation. We are presently performing studies where the fertility potential of oocytes is monitored, taking into account ovulation from the right/left ovary and laterality during two consecutive menstrual cycles.
In conclusion, ovulation from the right ovary occurs more frequently than from the left. Furthermore, the oocytes from the right ovary cause establishment of pregnancies more often than oocytes originating in the left ovary. This pattern is identical in a group of fertile and infertile women. The underlying mechanism is unknown but may be related to an enhanced output of oestradiol and testosterone by the corpus luteum on the right ovary.
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Notes |
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References |
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Submitted on April 3, 2000; accepted on June 8, 2000.