The data sources which may help strengthen the epidemiological evidence for the hormonal hypothesis of sex determination in man

William H. James

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


    Abstract
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The hypothesis that parental hormone levels around the time of conception partially control offspring sex ratios—though here taken to be true in substance—will need a great deal of work to specify with any accuracy. We do not know with any certainty which hormones are involved, nor how they are implicated. Answers to these two questions are only likely to emerge after prolonged experimental work. And it is fair to say that that work has not yet started. I assume that experimental workers will not embark on such a project until it is perfectly clear that there is a watertight case that mammalian parental hormone levels somehow influence offspring sex ratios. The present note indicates where further (human) evidence for that case will be found. In regard to human beings, much of the required information is held by clinics and registries not primarily concerned with reproductive biology. This point is illustrated here in regard to toxicology, teratology, radiation medicine, neurology, psychiatry, oncology, dermatology, rheumatology, occupational medicine and sports medicine as well as obstetrics and gynaecology. Tests (based on the hypothesis) are offered for intrauterine endocrine causes of malformations, and for pre- and post-natal endocrine causes of disease.

Key words: epidemiological evidence/hormone levels/offspring sex ratio


    Introduction
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Substantial quantities of data have been adduced to support the hypothesis that the sexes of mammalian (including human) offspring are partially controlled by the hormone levels of both parents around the time of conception (James, 1996Go, 1999aGo). There is now so much such evidence that one may infer a kernel of truth in the hypothesis. On that assumption, some directions for medical research will be suggested here. The point of this exercise is threefold. First I want to indicate why some reproductive biologists may need to persuade other scientists to part with data bearing on the hypothesis. Second, I shall offer methods for strengthening evidence that specified diseases and congenital malformations have hormonal causes. Third, some notes are given on the possibility that some disease conditions are related to the endocrine environment experienced by patients in utero. Notes are given on these points in order.

Scientific progress is sometimes made from the bootstraps up. If we knew more about the limitations of the hypothesis, we could infer more about its consequences for medical research. And as those consequences are explored, they will throw fresh light on the hypothesis. Indeed it will be suggested that—at least in respect of human beings—the epidemiological evidence relating parental hormones to offspring sex ratios will come not simply from reproductive biology, and areas familiar to reproductive biologists (obstetrics and gynaecology, teratology, toxicology, oncology and radiation biology) but from disciplines having no obvious connection with reproductive biology (e.g. psychiatry, neurology, dermatology, rheumatology, occupational medicine and sports medicine). So reproductive biologists will have to collaborate with (or at least scrounge data from) people with no immediate direct interest in reproductive biology. In other words, some reproductive biologists may need to become jacks of many medical trades before the task is complete. These points will be illustrated.

The hypothesis may provisionally be formulated thus: the sexes of mammalian offspring are causally associated with the level of R where R is a function of the form


where E, T, G and P are parents' sex-standardized levels of oestrogen, testosterone, gonadotrophins and progesterone. It may be acknowledged that this expression will presumably ultimately require mathematical refinement in the form of coefficients and exponents. Ex hypothesi, high levels of R (in either parent) are associated with boys, and low levels with girls. As noted above, it is almost certain that there is some truth in this, but the following questions are as yet unanswered:

  1. Do the various hormones play equal roles in some sense?
  2. Are the mother's and father's contributions equal in some sense?
  3. Are all these hormones involved (or are some merely markers for others or are all the hormones markers for non-endocrine factors)?
  4. Are any other hormones relevant (e.g. growth hormone or thyroid hormone)?
  5. What is the mechanism underlying the hypothesized hormonal determination of sex? I have suggested one (James, 1997a), but as far as I know, no attempt has been made to test it.
  6. Are the mechanisms the same in all mammalian species?

In the following numbered sections, I shall try to indicate how evidence (in the form of offspring and sibling sex ratios) from a range of medical specialities may be expected to add weight to the hypothesis that mammalian offspring sex ratios (proportion male at birth) are somehow controlled by parental hormone levels around the time of conception. Once sufficient such evidence has accumulated, the epidemiologist's work is complete, and experimental work will start on these problems.

1. Toxicology: testing the endocrine effects of suspect chemicals
Population sex ratios typically meander up and down slowly across time (Gini, 1955Go). The causes of these movements are unknown, but recent secular declines in sex ratios in many European populations, the USA, Canada and South America prompted the suspicion that endocrine disruptors were the cause. However, various lines of reasoning cast doubt on the suggestion that there has been a general phenomenon of this sort viz :

  1. Declines in sex ratios at birth have not been universal. There have been increases in recent years in some countries e.g. Australia, New Zealand, France, Ireland, and Spain (James, 2000aGo).
  2. In other countries, sex ratios have increased in one section of the population, and decreased in another. For instance, in the USA, white sex ratios declined while black sex ratios increased in the period 1969–1995 (Marcus et al., 1999Go). And in Italy, sex ratios decreased 1970–1995 in the metropolitan areas (those including the largest cities), and increased elsewhere (Astolfi and Zonta, 1999Go).

Nevertheless, it has become clear that a subsequent excess of female births is associated with paternal exposure to a number of chemicals e.g. the nematocide Dibromochloropropane (Potashnik and Yanai-Inbar, 1987Go), dioxin (Mocarelli et al., 1996Go, 2000Go), boron (James, 1999bGo) and probably vinclozolin (James, 1997bGo) as well as mixtures of unspecified agricultural chemicals (Restrepa et al., 1990Go; De Cock et al., 1995Go; Savitz et al., 1997Go). This being so, it is reasonable to propose that studies designed to assess potential deleterious effects of new chemical agents should routinely incorporate data on offspring sex ratio of exposed subjects. Such data may be of particular use in assessing the effects of long-term, low-level exposures on mammalian endocrine systems. It is to be hoped that data will be forthcoming not only on offspring sex ratios, but that—at least, if those sex ratios are skewed—workers will be prompted to assay the hormone profiles of exposed subjects. Moreover, most existing data report the offspring sex ratios of exposed men, or of exposed people: it is important to get data where only mothers have been exposed. It is not yet clear whether, in general, effects on offspring sex ratios differ according to sex of exposed parent, though this certainly seems to be true of dioxin (Mocarelli et al., 2000Go). In this context, it is worth remarking that the endocrine effects of boron on human beings need investigation. Oligospermia, decreased libido and sterility have reportedly been associated with men's exposure to boronated compounds (Krasovskii et al., 1976Go). Moreover these compounds have been associated with high gonadotrophin (G) in rats, and low testosterone (T) in mice, deer mice and rats (Fail et al., 1998Go). I suggest that the low offspring sex ratio of exposed men (James, 1999bGo) is due to a hormone profile associated with these compounds (a low T/G ratio?).

2. Teratology: testing hypotheses of maternal intrauterine endocrine causes
Most congenital malformations occur predominantly in one sex or the other (Lubinsky 1997Go; Arena and Smith, 1978Go): for example, neural tube malformations are more common in girls while heart malformations are more common in boys. This being so, one may ask whether some feature of the maternal intrauterine environment is responsible for both the malformation and the unusual sex ratio of the affected cases. This may be tested by examining the sex ratio of the unaffected siblings of the probands. If these siblings have a sex ratio that is biased in the same direction as that of the probands, one may conclude that the parents have a (hormonally driven) predisposition to produce children of that sex. In particular, this biased sibling sex ratio would suggest maternal intrauterine hormonal involvement in the aetiology of the malformation. Such an argument has been used to implicate high maternal androgen levels in polydactyly (James, 1998Go). Sibling sex ratios similarly suggest maternal hormonal involvement in transposition of the great arteries (James, 1999cGo) and oral clefts (James, 2000bGo). Lastly, sibling sex ratio data can be interpreted to suggest maternal hormonal involvement in cardiac malformations other than transposition (Knox, 1959Go). The data on sibling sex ratios (which would facilitate testing such hypotheses) lie untapped in malformation registries: I urge that work be initiated to test the above suggestions. Data on sibling sex ratios are needed in respect of all human sex-biased congenital malformations of unknown aetiology.

3. Radiation medicine: testing suspicions about microwave ovens, mobile phones and high voltage power lines
In this section, no reference will be made to the effects of ionizing radiation on offspring sex. However, non-ionizing radiation of various sorts has been reportedly associated with a variety of psychological symptoms (malaise, fatigue, dizziness, headache etc.) as well as low sperm counts and testosterone levels (James, 1997cGo). And there have been reports of significantly low offspring sex ratios to men working in high voltage power stations (Knave et al., 1979Go; Nordstrom et al., 1983Go; Mubarak and Mubarak, 1996Go); to women exposed to shortwave radiation (Larsen et al., 1991Go); to parents exposed to radiation from a radiolocation station (Kolodynski and Kolodynska, 1996Go) and to parents exposed to strong static and low frequency electromagnetic fields (Irgens et al., 1997Go). There is now enough evidence to suggest that some non-ionizing radiation has non-thermal effects: and indeed, ex hypothesi, to suggest that some non-ionizing radiation alters hormone levels. The present unease about mobile phones, microwave ovens and high voltage power lines might be allayed (or otherwise) by further data on the offspring sex ratios of exposed persons. If they prove to be skewed, further invasive testing, in the form of hormone assays, would be indicated. The most obvious present lacuna here is data on the hormone levels of men and women following exposure to non-ionizing radiation of various sorts. Since the above passage was written, it has been reported that (in conformity with my hypothesis) exposed men have low testosterone/gonadotrophin ratios (Grajewski et al., 2000Go).

4. Neurology and psychiatry
Some of the hormones that I have hypothesized to control offspring sex ratio also act as neurotransmitters in the brain (Smith et al., 1999Go). And there is evidence for the hypotheses that:

  1. oestrogen protects against schizophrenic symptoms in women (Seeman, 1996) and
  2. oestrogen is epileptogenic and progesterone antiepileptogenic (Herzog, 1999a, b).

Consistent with these hypotheses and mine, data have been adduced (James, 2000cGo) to suggest that: schizophrenic women produce a highly significant excess of daughters (ex hypothesi because schizophrenic women have low oestrogen levels); probands with `convulsions' or seizures have a significant excess of brothers (ex hypothesi because these probands and their mothers have a high oestrogen/progesterone ratio); and probands diagnosed as `photosensitive' (i.e. who have epileptiform EEG signs but no seizures) have a significant excess of sisters (ex hypothesi because these probands and their mothers have a low oestrogen/progesterone ratio).

These suggestions are new. They would be tested by further data on the hormone levels and offspring and sibling sex ratios of all three sorts of proband. Much such sex ratio data must lie in neurologic and psychiatric clinic registries.

5. Rheumatology
Systemic lupus erythematosus is more common in women than men. And male patients are reported to be hypoandrogenic (Mok and Lau, 2000Go). This being so, I should like to predict that the sex ratio (proportion male) of their offspring is low. Moreover, if this prediction is fulfilled, and if the low sex ratio predates disease onset, then the hypoandrogenicity may be interpreted as a potential (partial) cause of the disease.

6. Obstetrics and gynaecology
I have noted that many forms of placental pathology are associated with skewed offspring sex ratios (James, 1995Go). Highly significant excesses of male births are reportedly associated with abruptio placenta, placenta praevia, fatty liver of pregnancy and toxaemia; and highly significant female excesses reportedly occurred in placenta accreta and extrauterine pregnancy. The overall hypothesis is that maternal hormone profiles tending to produce offspring of one sex or the other share features of hormone profiles causing (or partially causing) the pathologies. As noted in that paper, the point could be tested by examining the extent to which maternal hormone concentrations control first, Fallopian tube motility, and second, infiltration by extravillous trophoblasts into the placental bed. The above argument (of intrauterine endocrine involvement) has been shown to be consistent with the excess of female offspring associated with hyperemesis gravidarum (James, 2000dGo) and may also apply to the excess of male offspring associated with pregnancies complicated by absent or reversed end-diastolic flow in the umbilical artery (Edwards et al., 2000Go).

Progress in this field has been slow: I believe that obstetrician-gynaecologists should reflect on the meaning of all these odd sex ratios. What is certain is that they have not arisen by chance.

7. Sports medicine
A highly significant U-shaped regression (P < 0.005) of offspring sex ratio on the weekly training mileage of male runners at the time of conception has been reported (Crawford et al., 1992Go). Runners who did no running in that week, and those who ran >50 miles, sired excesses of sons. Those who ran 30–50 miles sired an excess of daughters. It has been reported that within a group of male runners, free testosterone levels correlate negatively and highly significantly with the weekly training distance (Mackelvie et al., 2000Go). The above work on offspring sex ratios needs to be replicated: if the results of Crawford et al. (1992) are confirmed, I predict that runners with very high training mileages will not only have low testosterone levels, but proportionately even lower gonadotrophin levels. If this proves to be so, it may have some bearing on the overtraining syndrome.

8. Dermatology
Vaughan-Jones et al. report that infants born to mothers with dermatoses of pregnancy: (i) contain an excess of males, (ii) contain an excess of dizygotic twins, and (iii) have high birth weights (Vaughan-Jones et al., 1999Go).

I have noted (James, 2000eGo) that all three of these features would be explained if these mothers had high oestrogen and/or testosterone levels. The causes of these dermatoses are not established, so my suggestion may prove useful in elucidating their aetiology.

9. Oncology
Some remarks are made later about the offspring sex ratios of patients suffering, or destined to suffer, from non-Hodgkin's lymphoma, prostatic cancer and testicular cancer. Here comments will be confined to ovarian cancers.

Some forms of ovarian cancer (but perhaps not others) are more frequent on the right than the left. Moreover, some forms of ovarian cancer are associated with high levels of oestrogen (Cramer et al., 1994Go). Consistent with these findings, right-sided ovulation is reportedly associated with higher oestrogen levels than left-sided ovulation (Fukuda et al., 2000Go). And consistent with this latter finding, and my hypothesis (James, 1996Go), it was reported in 1927 by Schoner (following Hippocrates) that right-sided ovulation is significantly associated with the births of sons, and left-sided ovulation with the births of daughters (Schoner, 1927Go).

Thus one may speculate that those forms of ovarian cancer which show laterality have different hormonal antecedents from those which do not. Moreover the offspring sex ratios of the various forms of ovarian cancer may cast light on these differences. In particular, making the rather extensive assumption that all other things are equal, one would predict that women with those ovarian cancers which show a predilection for the right side would produce an excess of sons. Meanwhile, it would be useful to replicate Shoner's (1927) result (associating ovarian side with sex of offspring).

10. Occupational medicine
Significantly low paternal offspring sex ratios are reportedly associated with a number of occupations. In addition, some occupational exposures have been associated with low testosterone/gonadotrophin ratios. Both such features have been reported in respect of professional deep-water divers and pilots of high-performance aircraft and spacecraft. References are as follows.

Divers
Significantly low offspring sex ratios have been reported in respect of Australian abalone divers (Lyster, 1982Go) and Swedish Navy divers (Rockert, 1977Go). A reduction of about 50% in the testosterone levels of rats after exposure to 6 atmospheres absolute pressure has been reported (Rockert et al., 1978Go), and it has also been noted that testosterone levels in divers show a decrease after diving (Rockert and Haglid, 1983Go).

Pilots
Three reports suggest significantly low offspring sex ratios of pilots and astronauts exposed to unusual G-forces (Snyder, 1961Go; Goerres and Gerbert, 1976Go; Little et al., 1987Go). A report suggests that exposure to altered gravity (microgravity or centrifugation) affects the pituitary–gonadal axis in mammals (Ortiz et al., 2000Go); and reduced testosterone/gonadotrophin ratios have been reported in association with spaceflight in men (Strollo et al., 1998Go; Strollo, 1999Go).

It has been noted that men suffering from many forms of non-endocrine disease show a characteristic hormone profile viz. a low testosterone/gonadotrophin ratio (Semple, 1986Go). It is noteworthy that (as documented above) men have a similar profile following exposure to various deleterious chemicals, non-ionizing radiation, and various forms of adverse occupational exposure. One might ask whether such a hormone profile indicates sub-optimal immunological processes in men.

Testing hypotheses of endocrine causation of diseases
Patients with some diseases (e.g. multiple sclerosis and non-Hodgkin's lymphoma) are known to have unusual hormone profiles. The question arises: do these hormone profiles play any role in the aetiology of the diseases? In both cases, the answer is probably not. In both diseases, patients only produce children with skewed sex ratios after the disease has been diagnosed (Olsen and Brandt 1982Go; James 1994Go). Children produced before disease onset have normal sex ratios, so one might tentatively exclude hormones as causes of these diseases. On this interpretation, the unusual sex ratios of the children born after diagnosis are a (hormonally mediated) consequence of the disease or its treatment.

In contrast, consider prostatic cancer and testicular cancer. Men who later contract prostatic cancer reportedly sire a significant excess of sons (James, 1990Go). This is in conformity with my hypothesis and the suspected causal involvement of androgens in the disease (Bosland, 1988Go). Men with testicular cancer reportedly sire a significant excess of daughters both after and before disease onset (Møller, 1998Go; Jacobsen et al., 2000Go). Thus a hormonal cause of the disease is suggested (high gonadotrophin/testosterone ratios?). There is also evidence that some maternal intrauterine exposure of patients has a causal role in this disease: indeed it seems possible that such exposure is responsible for the patients' established unusual hormone profile (Petersen et al., 1999Go). Meanwhile further data are needed on the offspring sex ratios of men with these two sorts of cancer.

Testing the hypothesis that a disease is causally related to patients' intrauterine endocrine environment
Considerable attention has recently been given to the possibility that some pathological conditions (e.g. high blood pressure) are causally related to patients' experience in utero. The hypothesis presently receiving most attention is that nutritional deficit (as indicated by growth retardation) is responsible. But an alternative (or supplementary) hypothesis is that some sex-biased diseases are caused by unusual maternal intrauterine hormone profiles. The suggestion is analogous to that used above in connection with congenital malformations. And in just the same way, such a hypothesis may be tested by the sex ratio of probands' unaffected siblings. If they are skewed in the same direction as that of the probands, intrauterine hormone levels should be suspected.


    Summary
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 Abstract
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 Summary
 References
 
The hypothesis that mammalian parental hormone levels around the time of conception somehow are partially responsible for the sexes of the resulting infants (here treated as true in substance) stands in need of a very great deal of research. In regard to non-human mammalian species, experimental work will be undertaken if and when it seems worth doing. Little has so far been done, and it is to be hoped that experimentalists will eventually be stung into action by the continuing accumulation of human data. Much human data has emerged haphazardly over the last 20 years and the object of this paper is to direct readers to caches of further data (in the form of offspring and sibling sex ratios) which must lie untapped in clinic registries.


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