Characteristics of human ovulation in natural cycles correlated with age and achievement of pregnancy

Misao Fukuda1,3, Kiyomi Fukuda1, Claus Yding Andersen2 and Anne Grete Byskov2

1 Fukuda Ladies Clinic, 30–9 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


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
BACKGROUND: The aim of this study was to evaluate whether characteristics of human ovulation correlate with age and pregnancy potential. METHODS: Two groups of women with regular menstrual cycles were included (i.e. one fertile and one infertile group), which were divided into four age groups (<=29, 30–34, 35–39, 40 years). Monitoring included observations of follicular phase length, whether ovulations occurred from the left or right ovary, the pattern of ovulations in succeeding natural cycles and, in a subset of women, early follicular phase FSH concentrations. RESULTS: Ovulation moving from one ovary to the other in two consecutive cycles (i.e. contralateral ovulation) was inversely correlated with age, showing a ratio of contralateral ovulation per contra plus ipsilateral ovulations (C/C+I) of 62% in women <29 years, gradually decreasing to 42% in women >40 years. The ratio of right-sided ovulation per right plus left-sided ovulations (R/R+L) was unrelated to age and remained almost constant at a level of ~55%. The follicular phase length was inversely correlated with age, being 16.2 ± 2.9, 15.4 ± 2.9, 14.8 ± 2.8 and 13.7 ± 1.3 days in women < 29, 30–34, 35–39 and >40 years of age respectively. The follicular phase length was similar when comparing ovulations occurring from the right and left ovary, but comparing two successive cycles, the length of the follicular phase of the second cycle, showing contralateral ovulation, was shorter than ipsilateral ovulation with two consecutive ovulations in the same ovary. The pregnancy rate of the four groups decreased with age, being 14, 12, 5 and 3% respectively. The C/C+I ratio correlates with pregnancy rate and follicular phase length, and inversely correlates with basal FSH, whereas R/R+L is unrelated to age and pregnancy rate. CONCLUSIONS: Human ovulation shows characteristics related to age. The interaction between the two ovaries seems to be most pronounced in the younger years, where ovulations jump from one ovary to the other more frequently than later on in life. The C/C+I ratio shows a clear correlation with age and pregnancy rate.

Key words: age/contralateral versus ipsilateral ovulations/follicular phase length/pregnancy/right-sided versus left-sided ovulations


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
It is generally assumed that ovulation from each of the two ovaries occurs approximately the same number of times. Different studies have shown that right-sided ovulations occur with the same frequency as left-sided ovulations: 81/156 natural cycles, 52% (Balasch et al., 1994Go); 210/410, 51% (Fukuda et al., 1996Go); or that the right ovary tends to undertake more ovulations than the left ovary: 62/97, 64% (Potashnik et al., 1987Go); 312/572, 54.5% (Check et al., 1991Go). As suggested in a review by Baker and Spears, there do not seem to be data supporting a preference to the left ovary (Baker and Spears, 1999Go). However, a recent study reported that ovulation was right-sided in 273 of 477 cycles (57.2%) (Jarvela et al., 2000Go). Moreover, our previous study evaluated in >2000 cycles, including both fertile and infertile women, demonstrated that the right ovary supports ovulation (55%) more frequently than the left ovary (45%) (Fukuda et al., 2000bGo).

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, 1977Go; Hodgen, 1982Go; Marinho et al., 1982Go; Gougeon and Lefevre, 1984Go), from the same side (i.e. ipsilaterally) (Werlin et al., 1986Go) or at random (Clark et al., 1978Go; Check et al., 1991Go). 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., 1973Go; Fukuda et al., 1996Go). A significantly longer follicular phase of ipsilateral ovulations compared with contralateral ovulations was observed in infertile women (Potashnik et al., 1987Go; Fukuda et al., 1996Go, 1998Go). 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, 2000Go). 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.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
This is a retrospective study including two different groups of women, one fertile and one infertile. Women were classified as infertile when they wished to conceive but failed after at least one year without using any contraceptive measure and attended our clinic complaining of infertility. Women in the fertile group had all given birth to at least one live born infant. Women in both groups showed regular menstrual cycles (mean ± SD: 29.4 ± 3.1 days, range 23–39) without ovulation disorder and had two intact ovaries without ovarian cysts.

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 22–45) 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 1–10). 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, 30–34, 35–39 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., 1996Go) 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 20–50). 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 7–14 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 (38–47 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, {chi}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.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Follicular phase length in right-sided and left-sided ovulations and contralateral and ipsilateral ovulations with ageing in infertile women
All groups taken together showed that the average follicular phase length correlated inversely with age, decreasing from 16.2–13.7 days (Table IGo). The follicular phase length was unrelated to whether the dominant follicle developed in the right or left ovary, being 15.5 ± 2.9 days for right-sided ovulations and 15.3 ± 2.9 for left-sided ovulations (Table IGo).


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Table I. Follicular phase length (day) in right-sided (R) and left-sided (L) ovulations and contralateral (C) and ipsilateral (I) ovulations with ageing in infertile women. Values are presented as mean ± SD (n)
 
The follicular phase length in left-sided ovulation at age <29 years was slightly longer than that of right-sided ovulationm, but at >=30 years of age the follicular phase length in ovulations from the right ovary seemed to be longer than that of left-sided ovulation, although this difference did not reach significance. The follicular phase length in contralateral ovulation (15.2 ± 2.9) was overall significantly shorter than that of ipsilateral ovulation (15.6 ± 2.8) (P = 0.0274). When the age was confined to <39 years, the follicular phase length in contralateral ovulation (15.2 ± 2.9) was significantly shorter than that of ipsilateral ovulation (15.7 ± 2.8) (P = 0.0169). This difference was most pronounced in younger women and diminished with age, almost disappearing in the age group >40 years (Table IGo).

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 IIGo). Observations in the fertile as well as the infertile group were included. At almost all ages from 20–50 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 30–34 and 35–39 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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Table II. Right-sided (R) and left-sided (L) ovulations with ageing during 2090 natural cycles in fertile and infertile women
 
The ovulation pattern in succeeding cycles in relation to age was observed in women in their natural cycles 1103 times (Table IIIGo). Data included observations in fertile and infertile women. The frequency of contralateral ovulations showed an inverse correlation with age, being similar in fertile and infertile women. The frequency of contralateral ovulations in the younger age group of <29 years showed a relatively high ratio of 62%, being reduced to 57% in the age group 30–34 and 53% in the group 35–39 years. In women >40 years, C/C+I was further reduced to 42%. The overall mean C/C+I including all age groups in both fertile and infertile women was 56% (619/1103), which was significantly higher than 50% (P = 0.004).


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Table III. Contralateral (C) and ipsilateral (I) ovulations with ageing during 1103 natural cycles in fertile and infertile women
 
Basal FSH on day 3 of the menstrual cycle at the age of <29 years was 6.2 ± 1.4 IU/l, increasing to 6.4 ± 1.3, 7.7 ± 2.7 and 9.2 ± 2.3 IU/l in the age groups 30–34, 35–40 and >40 years respectively. The stepwise regression analysis of basal FSH showed a statistically significant linear correlation with age (P < 0.00005, r = 0.38). The stepwise regression analysis of follicular phase length showed a significant inverse linear correlation with age (P < 0.00005, r = 0.25) and that of the C/C+I ratio also indicated a significant inverse linear correlation with age (P < 0.0002, r = 0.77).

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 30–34 group, 5% (14/267) in the 35–39 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 30–39, 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 1Go.



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Figure 1. The relationship between basal FSH (IU/l), follicular phase length (day), pregnancy rate per cycle (%), right-sided ovulation per right plus left-sided ovulations (R/R+L), contralateral ovulation per contra plus ipsilateral ovulations (C/C+I) with ageing in fertile and infertile women.

 
Mean age, basal FSH, follicular phase length, the ratio of right-sided ovulations and the ratio of contralateral ovulations of pregnant women and non-pregnant women <39 years of age treated with IUI or IVF are shown in Table IVGo. Pregnant women showed younger age, lower basal FSH, longer follicular phase length and a higher ratio of contralateral ovulations than non-pregnant women. The ratio of right-sided ovulations was similar between pregnant and non-pregnant women.


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Table IV. Mean age, basal FSH, follicular phase length, right-sided ovulation per right plus left-sided ovulations (R/R+L) and contralateral ovulation per contra plus ipsilateral ovulations (C/C+I) of pregnant and non-pregnant women (<39 years of age) treated with IUI or IVF. Values are presented as mean±SD
 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
The present study found that ovulation characteristics were age related and independent of whether a fertile or infertile group was assessed. Women <29 years old show predominantly a pattern of ovulations altering between the two ovaries in consecutive cycles, whereas ovulations, as age increases, more frequently occur in the same ovary in two consecutive cycles. In contrast, the frequency of right-sided ovulations remains almost constant over the years, showing that the right ovary is constantly more active than the left and that ~55% of all ovulations occur from the right ovary.

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, 1977Go; Clark et al., 1978Go; Hodgen, 1982Go; Marinho et al., 1982Go; Gougeon and Lefevre, 1984Go; Check et al., 1991Go; Ecochard and Gougeon, 2000Go).

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, 2000Go). This follicular phase length corresponds to that observed in the middle age group (i.e. 30–39 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 35–39 year age group (Ecochard and Gougeon, 2000Go).

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., 1996Go, 1999Go, 2000aGo) and clomiphene citrate-stimulated cycles (Fukuda et al., 1998Go, 1999Go, 2000aGo). 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., 2000bGo). 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 37–38 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., 1987Go, 1992Go; Gosden et al., 1989Go; Gosden and Faddy, 1994Go; Gougeon et al., 1994Go; Faddy and Gosden, 1995Go; Gougeon, 1996Go; Broekmans et al., 1998Go; Scheffer et al., 1999Go). 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.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
We thank the attending nurses and other participants as volunteers for their long lasting efforts of up to 10 months. We heartily appreciate their contribution to this investigation. Without their kind co-operation this work could not be accomplished.


    Notes
 
3 To whom correspondence should be addressed. E mail: fukuda8767{at}gem.bekkoame.ne.jp Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Baker, S.J. and Spears, N. (1999) The role of intra-ovarian interactions in the regulation of follicle dominance. Hum. Reprod. Update, 5, 153–165.[Abstract/Free Full Text]

Balasch, J., Penarrubia, J., Marquez, M. et al .(1994) Ovulation and ovarian cancer. Gynecol. Endocrinol., 8, 51–54.[ISI][Medline]

Broekmans, F.J., Scheffer, G.J., Bancsi, L.F. et al .(1998) Ovarian reserve tests in infertility practice and normal fertile women. Maturitas, 30, 205–214.[ISI][Medline]

Check, J.H., Dietterich, C. and Houck, M.A. (1991) Ipsilateral versus contralateral ovary selection of dominant follicle in succeeding cycle. Obstet. Gynecol., 77, 247–249.[Abstract]

Clark, J.R., Dierschke, D.J. and Wolf, R.C. (1978) Hormonal regulation of ovarian folliculogenesis in rhesus monkey: I. Concentration of serum luteininzing hormone and progesterone during laparoscopy and patterns of follicular development during successive menstrual cycles. Biol. Reprod., 17, 779–783.

Dukelow, W.R. (1977) Ovulatory cycle characteristics of Macaca fasicularis. J. Med. Primatol., 6, 33–42.[ISI][Medline]

Ecochard, R. and Gougeon, A. (2000) Side of ovulation and cycle characteristics in normally fertile women. Hum. Reprod., 15, 752–755.[Abstract/Free Full Text]

Faddy, M.J. and Gosden, R.G. (1995) A mathematical model of follicle dynamics in the human ovary. Hum. Reprod., 10, 770–775.[Abstract]

Faddy, M.J., Telfer, E. and Gosden, R.G. (1987) The kinetics of pre-antral follicle development in ovaries of CBA/Ca mice during the first 14 weeks of life.Cell. Tissue Kinet., 20, 551–560.[ISI][Medline]

Faddy, M.J., Gosden, R.G., Gougeon, A. et al .(1992) Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Hum. Reprod., 7, 1342–1346.[Abstract]

Fukuda, M., Fukuda, K., Yding Andersen, C. and Byskov, A.G. (1996) Contralateral selection of dominant follicle favours pre-embryo development. Hum. Reprod., 11, 1958–1962.[Abstract]

Fukuda, M., Fukuda, K., Yding Andersen, C. and Byskov, A.G. (1998) Contralateral ovulation shortens follicular phase length and favours pre-embryo development during ovarian stimulation with clomiphene citrate. Hum. Reprod., 13, 1590–1594.[Abstract]

Fukuda, M., Fukuda, K., Yding Andersen, C. and Byskov, A.G. (1999) Anovulations in an ovary during two menstrual cycles enhance the pregnancy potential of oocytes matured in that ovary during the following third cycle. Hum. Reprod., 14, 96–100.[Abstract/Free Full Text]

Fukuda, M., Fukuda, K., Yding Andersen, C. and Byskov, A.G. (2000a) Does anovulation induced by oral contraceptives favor pregnancy during the following two menstrual cycles? Fertil. Steril., 73, 742–747.[ISI][Medline]

Fukuda, M., Fukuda, K., Yding Andersen, C. and Byskov, A.G. (2000b) Right-sided ovulation favours pregnancy more than left-sided ovulation. Hum. Reprod., 15, 1921–1926.[Abstract/Free Full Text]

Gosden, R.G. and Faddy, M.J (1994) Ovarian aging, follicular depletion and steroidogenesis. Exp. Gerontol., 29, 265–274.[ISI][Medline]

Gosden, R.G. Telfer, E. and Faddy, M.J. (1989) Ovarian cyclicity and follicular recruitment in unilaterally ovariectomized mice. J. Reprod. Fertil., 87, 257–264.[Abstract]

Gougeon, A. (1996) Regulation of ovarian follicular development in primates: facts and hypotheses. Endocr. Rev., 17, 121–155.[ISI][Medline]

Gougeon, A. and Lefevre, B. (1984) Histological evidence of alternating ovulation in women. J. Reprod. Fertil., 70, 7–13.[Abstract]

Gougeon, A., Ecochard, R. and Thalabard, J.C. (1994) Age-related changes of the population of human ovarian follicles: increase in the disappearance rate of non-growing and early-growing follicles in aging women. Biol. Reprod., 50, 653–663.[Abstract]

Hodgen, G.D. (1982) The dominant ovarian follicle. Fertil. Steril., 38, 281–300.[ISI][Medline]

Jarvela, I., Nuojua-Huttunen, S. and Martikainen, H. (2000) Ovulation side and cycle fecundity: a retrospective analysis of frozen/thawed embryo transfer cycles. Hum. Reprod., 15, 1247–1249.[Abstract/Free Full Text]

Marinho, A.O., Sallam, H.N., Goessens, L. et al .(1982) Ovulation side and occurrence of mittelschmerz in spontaneous and induced ovarian cycles. Brit. Med. J., 284, 632.[ISI][Medline]

Potashnik, G., Insler, V. and Meizner, I. (1987) Frequence, sequence, and side of ovulation in women menstruating normally. Br. Med. J., 294, 219.

Scheffer, G.J., Broekmans, F.J.M., Dorland, M. et al .(1999) Antral follicle counts by transvaginal ultrasonography are related to age in women with proven natural fertility. Fertil. Steril., 72, 845–851.[ISI][Medline]

Wallach, E. E., Virutamasen, P. and Wright, K.H. (1973) Menstrual cycle characteristics and side of ovulation in the rhesus monkey. Fertil. Steril., 24, 715–721.[ISI][Medline]

Werlin, L.B., Weckstein, L., Weathersbee, P.S. et al .(1986) Ultrasound: a technique useful in determining the side of ovulation. Fertil. Steril., 46, 814–817.[ISI][Medline]

Submitted on April 17, 2001; accepted on September 14, 2001.