This study demonstrates that the age of women who conceived in the present cohort is associated with different ovulation patterns. Three consecutive menstrual cycles on the left ovary resulted in a significantly higher age than the other ovulatory patterns, which is new information that has not previously been reported (20). This pattern also resulted in an increased frequency of girls born when compared to other ovulatory patterns. This data confirms and extends an earlier study (20) and emphasizes that a menstrual cycle cannot be viewed as one independent entity as one menstrual cycle is affected by the activity in that particular ovary during the two previous cycles.
We found that women who conceived following a LLR ovulation pattern were significantly younger than the age of women who conceived following a LLL ovulation pattern. Furthermore, the LLR ovulation pattern favoured a higher frequency of infant boys showing a remarkably high sex ratio of 2.464, which was significantly higher than all the other ovulation patterns. This might be associated with the highest pregnancy potential of the LLR pattern (20). In contrast, the LLL ovulation pattern was associated with the oldest average age and the possibility of having a girl.
Furthermore, when only considering two consecutive menstrual cycles, the LR ovulation pattern and contralateral ovulation resulted in a younger mean age and an augmented male offspring ratio in the group of infertile women. Moreover, right-sided ovulation favoured male offspring in the infertile and infertile + fertile women groups irrespective of age, which was, however, not observed in fertile women.
Taken together, the ovulatory pattern through three consecutive cycles appears to affect the health of the preovulatory follicles and the enclosed oocyte in ways not previously recognised and suggest that new mechanisms exert subtle effects on pregnancy potential.
This study also demonstrates that the right and left ovaries are not equally capable of producing viable oocytes with pregnancy potential. It appears that oocytes deriving in the right ovary more often result in a baby. Although the two ovaries are not vascularized in exactly the same way and therefore may receive slightly different hormonal stimulation, it is difficult to explain this difference.
The present study is unable to reveal why women at a younger age conceive when an ovulation pattern consisting of RLR or LR (i.e. contralateral ovulation) is occuring compared to other ovulation patterns such as LLL, RR or LL (i.e. ipsilateral ovulation). Additionally, no differences in mean age at conception between right and left-sided ovulations were observed. These findings are congruent with the previous report (16) indicating that the proportion of contralateral ovulation per total number of ovulations decreases with age although the proportion of right-sided ovulations per total ovulations remain almost constant, ~ around 55 % irrespective of age. Moreover, the present finding may be interpreted as the offspring sex ratio decreasing with maternal age (22, 23), suggesting that the lower offspring sex ratio of reproductive aged women may be associated with more frequent ipsilateral ovulations than contralateral ovulation during advanced reproductive ages.
Weinberg et al. (24) reported an association between the sex ratio of offspring and the length of the follicular phase, indicating that a mean follicular phase length of 15.4 days in 69 women resulted in more male than female infants, whereas a mean follicular phase of 17.6 days in 64 cycles produced more females. However, no consistent pattern in the sex ratio at birth associated with the length of the follicular phase was found in a large cohort of 947 singleton live-born infants (25). Helle (26) reported that women with long menstrual cycles tend to have more daughters (175 women and 367 daughters) supporting the follicular phase hypothesis (24). In a cohort of 123 infertile women it was reported that the length of the follicular phase in 235 ovulation cycles in which ovulation occurred in the opposite ovary compared to the preceding cycle (15.2 ± 3.2 days) was significantly shorter than that of 175 ipsilateral ovulation cycles (15.8 ± 2.8). It was also found that contralateral ovulation favours pre-embryo development compared to ipsilateral ovulations (12), which was also seen in CC cycles (13). The present study found that the sex ratio of infants after contralateral ovulation cycles was significantly increased than that of ipsilateral ovulation cycles. Therefore, the finding of increased proportion of females after a longer follicular phase may be associated with ipsilateral ovulations.
In some mammalian species, for instance Mongolian gerbils, more males are conceived with oocytes derived from the right ovary than those from the left ovary (26). It has been shown that right-sided ovulation favours pregnancy more than left-sided ovulation (18). James et al. (28) proposed that high concentrations of testosterone and oestrogen around the time of conception increase the probability of a son. The present study indicated that right-sided ovulation does not seem to show higher offspring sex ratios than left-sided ovulation in fertile women, whereas right-sided ovulation shows significantly higher offspring sex ratio compared to left-sided ovulation in infertile and infertile + fertile women. The reason for this difference is at present unknown.
The offspring sex ratio of 1.048 in fertile women is around the same as that of 1.043 in our previous study (2) while the sex ratio of 1.161 in infertile women seems to be higher than that of the general population. The reason for this difference is unknown. However, it was reported that the offspring sex ratio following infertility treatment such as IUI or IVF is high (28), which is consistent with the present results.
In the present study the percentage of non-smoking fertile couples was 32% (220/684), which was near to the value of 30% in our previous study (2). In contrast, the percentage of non-smoking infertile couples in the present study was 45% (87/192), which was significantly (p=0.0226) higher than that of fertile couples. Therefore, a higher percentage of non-smoking infertile couples may be one of the reasons why a higher offspring sex ratio is seen in this group of infertile couples compared to the fertile couples.
There may be some confounding factors affecting the ovulation patterns. BMI is one such possible factor. We have only BMI available for a fraction of women in this study and are therefore unable to evaluate it as a possible factor.
The present study is a retrospective analysis from 1990 to 2012 covering a relatively long period. Therefore, the results may be inhomogeneous and reveal a clustering of outcomes that can be explained simply by random chance. However, we merely observed naturally occurring events of ovulation side and thus we believe these findings are unbiased.
The mechanism behind these observations is not yet clear but it may relate to levels of oestradiol and/or testosterone (30, 31) or oestradiol/androgen ratio (12, 32) at the time of conception. Also, cortisol prior to conception (33), glucose level at implantation (34) and/or adrenal androgen during pregnancy (35) may be associated with offspring sex ratios. Further research is needed to discover the reasons for these differences.