‘Over-ripeness ovopathy, sex ratio increase and sex ratio reversal a challenging hypothesis for sex ratio modulation’

An alternative interpretation

William H. James

The Galton Laboratory, University College London, Wolfson House, 4 Stephenson Way, London NW1 2HE, UK


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It is suggested here that Jongbloet has misinterpreted data on the variation of sex ratio with maternal age, social class, placental dysfunction, twinning and season. When all these matters are considered, it is not clear whether there is any truth in his supposition that male fetuses are generally conceived in suboptimal conditions. Finally, it is suggested that there is a circularity in his presentation of his concept of sex ratio ‘reversal’.

Key words: fertile interval/hormonal profile/male and female conception/ovopathy/sex ratio


   
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Jongbloet’s hypothesis (Jongbloet, 2004Go), as I understand it, originated from two observations: (i) the regression of the sex ratio (proportion of males at birth) on the time of insemination within the fertile interval (those days within the cycle when coitus is associated with a non-zero probability of conception) is U-shaped, the probability of male conceptions being greater at the beginning and end of this interval; and (ii) the probability of spontaneous abortion is also greater with respect to conceptions at the beginning and end of this fertile interval.

Both these observations may be regarded as established (e.g. James, 2000aGo; Gray et al., 1985Go, respectively). Therefore, one may infer that within the cycle, female zygotes, in contrast to male zygotes, are more likely to be formed at an optimal time. This inference may be construed as the explanation for a number of phenomena, e.g. the reduced survival of males before and after birth, the excess of males among premature babies, and the high proportion of males with some types of congenital malformation.

However, Jongbloet has sought to expand this inference to conclude that, in general, adverse maternal circumstances are associated with male births. This seems questionable, and conflicts with the hypothesis of Trivers and Willard (1973Go) which has withstood testing in many non-primate species. It also seems to conflict with the direct finding that physically strong mothers reportedly bear strikingly higher proportions of sons than weaker mothers in a food-stressed community (Gibson and Mace, 2003Go). I deal here with some of the evidence invoked by Jongbloet in this context.

Placental dysfunction. Jongbloet (2004Go) cites myself (James, 1995aGo) to substantiate the claim that there is a male bias in the outcome of pregnancies associated with placental dysfunction. As noted in the cited paper, this is not a universal finding. Some sorts of dysfunction are associated with male offspring (placenta praevia, fatty liver of pregnancy and toxaemia); others are associated with female offspring (placenta accreta and extrauterine pregnancy).

Twinning. Jongbloet (2004Go) suggests that there is a male-biased perinatal mortality in twins, especially monozygotic (MZ) ones. This has been denied by Hall (2003Go). Indeed, this author follows my suggestion (James, 1988Go) that the established female excess in MZ twins is associated with anomalous X-chromosome inactivation. If this were so, then the variation of sex ratios of live born MZ twins by placentation (James, 1980Go) is a phenomenon which falls outside the scope of general theorizing about sex ratios.

Socio-economic status. Jongbloet (2004Go) writes that the common determination by ovopathy (of sex ratio and pathology) explains: ‘The increased odds for delivering progeny with developmental defects and a male child when the socio-economic level decreases from high to moderate...’ In a review of this matter, I concluded that ‘parental social class per se seems to have only a minimal effect on the sex ratio at birth’ (James, 1987Go). I know of no large sample which would support Jongbloet here.

Advanced maternal age. Jongbloet (2004Go) writes that his hypothesis explains the high secondary sex ratios of offspring of mothers at ‘very young and advanced maternal age’. I know of no large human data set in which the offspring of older mothers do have a high sex ratio. Moreover, the magnitude of the variation of the sex ratio by maternal age (as by social class) is so small as to be apparently valueless in suggesting (or confirming) causes.

Season. Jongbloet (2004Go) emphasizes that pre-ovulatory over-ripeness is seasonally bound. There is no doubt that in some species, offspring sex ratios at birth show substantial seasonal variation. However, in man, such variation is minuscule in large samples (James, 1987, p. 723). Gilbert and Danker (1981Go), for instance, failed to find significant such variation in a sample of 20 million births. The inference is that pre-ovulatory over-ripeness, if it were related to the sex ratio, has little to do with season. This conclusion is strengthened by data published by Cagnacci et al. (2003Go). These authors showed that though there is no appreciable variation in sex ratio at birth, there is significant variation in sex ratio at conception. Moreover, this seasonal variation in sex ratio at conception has a single peak in the autumn and a single trough in early spring—both features of the seasonal curve of fertility. These authors concluded that (contrary to Jongbloet) males are conceived preferentially at times that are favourable for conception. In response, Jongbloet (2003Go) claimed that this challenges the established U-shaped regression of sex ratio on the cycle day of conception. I think Jongbloet’s argument is invalid here and I agree with Cagnacci (2003Go) that Cagnacci’s data ‘simply do not seem to fit [Jongbloet’s] hypothesis’.

Jongbloet (2004Go) writes that ‘The well-known secular decrease of the SSR (secondary sex ratio) in contemporary industrialized countries.... has been explained by improvements in nutritional standards, general health and more safe family planning, in other words in a decrease of the rate of conceptopathology...’. There are two points to be made here. (i) In recent years, the SSR has declined in some industrial countries and increased in others (e.g. Australia, Italy, France, Ireland, Spain and New Zealand). Moreover, in the USA, in 1969–1995, the live birth sex ratio increased in terms of black births and decreased in terms of white births (for references, see James, 2000bGo). No existing explanation (Jongbloet’s or otherwise) can satisfactorily accommodate these data. (ii) It has been argued that the recent secular declines in sex ratios in some countries may be due to exposure to hormone disruptors such as dioxin (rather than to changes in parental well-being). In fact, as noted above, the causes of this secular variation have not been established.

So far, I have dealt with Jongbloet’s treatment of sex ratio variation by maternal variables. It is now established that paternal exposure to some deleterious chemicals (e.g. dioxin) is followed by the births of significant excesses of daughters (e.g. Mocarelli et al., 2000Go). It is useful to examine the response of Jongbloet et al. (2002Go). They suggested (p. 1) that paternal exposure is associated with poor quality of sperm which in turn is associated with post-ovulatory over-ripeness and male-preferential prenatal loss. They claim that this hypothesis is more plausible than mine. (I have suggested that parental hormone levels partially control the probability of fertilization by X- or Y-bearing sperm; e.g. James, 1996.) However, in the absence of data on sexed spontaneous abortions, I cannot see evidence to favour Jongbloet’s hypothesis over mine here. Meanwhile it is worth remarking that (on the basis of the reported hormone profile of exposed men), I predicted that they would sire an excess of daughters (James. 1995bGo).

This is not the only confirmed prediction that has been based on my hypothesis. Here I describe three others.

(i)Ollier et al. (1989Go) assayed the testosterone levels of 71 men with rheumatoid arthritis and 138 healthy controls. These workers found that in both patients and controls, the men who were HLA B15 positive had the lowest mean testosterone levels. Accordingly, Astolfi et al. (2001Go) tested a prediction based on my hypothesis, namely that men carrying HLA B15 should sire a high proportion of daughters. The prediction was confirmed and these authors wrote ‘These results suggest an effect of HLA B15 on the secondary sex ratio mediated by a low testosterone level’.

(ii)Substantial quantities of data have been adduced to support the hypothesis that R, the ratio of the lengths of the second (2D) and fourth (4D) fingers (where R = 2D/4D), is negatively correlated with men’s testosterone concentrations (e.g. Manning, 2002Go). Accordingly, I predicted that men’s R values should correlate negatively with their offspring sex ratios (James, 2001Go). This prediction has been confirmed by Manning et al, (2002Go).

(iii)It was evident that the intrauterine position of rodents is associated with their subsequent adult hormone levels: females adjacent in utero to two males (2M females) are more androgenized than females adjacent to two females (0M females). This is due to the transference of testosterone from male fetuses to adjacent female ones (Ryan and Vandenbergh, 2002Go). So I predicted that the sex ratio of offspring of 0M females would differ from that of 2M females (James, 1989Go). The point has since been tested and my prediction confirmed on female gerbils (Clark et al., 1993Go; Clark and Galef, 1994Go) and mice (Vandenbergh and Huggett, 1994Go)

The above confirmed predictions raise the question of whether, in principal, Jongbloet could have made such predictions on the basis of his hypothesis. He is committed to the notion that adverse circumstances are associated with male offspring; therefore, the observation that some adverse circumstances are nevertheless associated with female offspring has led him to invoke the notions of sex ratio ‘reversal’ and ‘inverted dose–response gradient’. He writes that ‘this is not a theoretical construction to explain the epidemiological findings, as suggested by dissenting opponents..’. It is important to understand the point that these opponents were trying to make, and to assess whether it has been met by Jongbloet.

Jongbloet’s notion (Jongbloet, 2004Go) is that adverse circumstances cause the formation of male zygotes, and that, after some undetermined optimum level of adversity has been reached, more severe circumstances cause these male zygotes to be preferentially spontaneously aborted (resulting in a reduction in the live birth sex ratio, which Jongbloet calls ‘sex ratio reversal’). As far as I can see, we could only know whether this explanation were correct if we had data on the sexes of spontaneous abortions at different levels of adversity. In general, we do not have such data, so, if I am correct, Jongbloet would have been unable to make the predictions cited above. He might have predicted that sex ratio changes were to be expected—but not in which direction. It should be emphasized that this line of reasoning does not imply decisively that his hypothesis is false, but it does suggest that mine is more readily testable. I contend that we cannot know whether there is any truth in his hypothesis until data are available on the sexes of the associated spontaneous abortions. For only by that means can we learn whether sex ratio ‘reversal’ occurs in accordance with the dose–response fallacy. In the title of his paper, Jongbloet (2004Go) uses the term ‘sex ratio reversal’; this suggests a circular argument, i.e. one that assumes what is purportedly being demonstrated. To escape this conclusion, I suggest that Jongbloet should indicate what imaginable empirical findings would falsify his hypothesis. If an explanation cannot be falsified by any findings, then it belongs to metaphysics, not science. This, I think, is what the ‘dissenters’ had in mind.

Summary
(i) I think Jongbloet may have misinterpreted data on variation of sex ratio with maternal age, social class, placental dysfunction, twinning and season.

(ii) I think he should specify what findings would falsify his hypothesis.


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