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• A Simple Non-Invasive Method of Testing Whether High Intrauterine Testosterone Concentrations Are a Cause of Amyotrophic Lateral Sclerosis : A Response to Papers of Vivekananda et al.
  William H James
  Published on: 2 June 2011

• Published on: 2 June 2011

  A Simple Non-Invasive Method of Testing Whether High Intrauterine Testosterone Concentrations Are a Cause of Amyotrophic Lateral Sclerosis : A Response to Papers of Vivekananda et al.

  • William H James, Research Scientist

  Vivekananda et al(1)report that when controlled for sex, cases of sporadic amyotrophic lateral sclerosis (ALS) have a lower mean finger length ratio R [where R = (2D / 4D) and 2D and 4D are the lengths of the 2nd and 4th digits respectively] than healthy controls. These authors interpret their finding as indicating prenatal involvement of high concentrations of intrauterine testosterone, T. However, their interpretation...

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  Vivekananda et al(1)report that when controlled for sex, cases of sporadic amyotrophic lateral sclerosis (ALS) have a lower mean finger length ratio R [where R = (2D / 4D) and 2D and 4D are the lengths of the 2nd and 4th digits respectively] than healthy controls. These authors interpret their finding as indicating prenatal involvement of high concentrations of intrauterine testosterone, T. However, their interpretation is not the only one : another possibility arises from the reported variation of R with adult sex hormone levels(2). So (some cases of) ALS may arise either as a consequence of high maternal T levels, or of high levels of the patient's own postnatal T (or both). Here I offer a means of discriminating between these two hypotheses.

  I have adduced substantial quantities of data to support the hypothesis that mammalian (including human) offspring sex ratios at birth are partially controlled by parental hormone levels around the time of conception(3-5). Ex hypothesi, high levels of T are associated with the subsequent births of sons. So if my hypothesis and that of Vivekananda et al(1) were both correct, that would explain why probands with ALS contain an excess of males(6,7). Moreover, if both hypotheses were correct, then ALS probands should have a statistical excess of brothers. The point should be tested.

  An illustrative use of this form of argument provided support for Baron-Cohen's hypothesis(8) that one cause of autism is high intrauterine T concentrations. If his hypothesis and mine were both correct, then autistic probands should have an excess of brothers. This has been reported(9) and twice replicated(10,11), giving strong support to Baron- Cohen's hypothesis. So it would be interesting to see data on the sib sex ratio of ALS probands.

  Another approach to the present problem may be via the variable of parity or birth order. First-borns, as contrasted with later-borns, are reportedly exposed to higher levels of testosterone in early(12), and late(13) pregnancy. So if the hypothesis of Vivekananda et al(1) were correct, there should be a statistical excess of first-borns among ALS probands. This point has been tested, also by Vivekananda and co- workers(14), and they reported a non-significant result. However this latter conclusion may be indecisive : there are pitfalls in the interpretation of birth order studies.

  1. In the first place, Vivekananda et al(14) were testing for a positive birth order effect (viz one in which the risk correlates positively with birth order). So they omitted a substantial quantity of their data viz : all their affected sibships of size less than 4 because these sibships might have been incomplete and thus be uninformative about the effect. However the purpose at present is to test for a negative birth order effect : viz one in which the risk correlates negatively with birth order and which may therefore be manifest in incomplete sibships of size 2+. So I suggest that these workers should test their complete material without omitting the shorter sibships.

  2. In the second place, these workers give no explanation for their choice of statistical test : in particular, and in the absence of a control group, it is not clear that it is as powerful as other more conventional tests e.g. that of Haldane and Smith(15). So I suggest that their entire material should be submitted to that test. If a significant birth order effect is indicated, that will give strong support to the hypothesis of Vivekananda et al(1) that one cause of amyotrophic lateral sclerosis is high intrauterine levels of testosterone.

  References

  1. Vivekananda U, Manjalay ZR, Garesalingam J et al. Low index to ring finger length in sporadic ALS supports prenatally defined motor neuronal vulnerability. J Neurol Neurosurg Psychiatr 2011;82:635-637

  2. Manning JT, Scutt D, Wilson J et al. The ratio of 2nd to 4th digit lengths : a prediction of sperm numbers and concentrations of testosterone, luteinizing hormone and oestrogen. Hum Reprod 1998;13:3000- 3004

  3. James WH. Evidence that mammalian sex ratios at birth are partially controlled by parental hormone levels at the time of conception. J Theor Biol 1996;180:271-286

  4. James WH. Further evidence that mammalian sex ratios are partially controlled by parental hormone levels around the time of conception. Hum Reprod 2004;19:1250-1256

  5. James WH. Evidence that mammalian sex ratios at birth are partially controlled by parental hormone levels around the time of conception. J Endocrinol 2008;198:3-15

  6. McCombe PA, Henderson RD. Effects of gender in amyotrophic lateral sclerosis. Gender Med 2010;7:557-570

  7. Logroscino G. Incidence of amyotrophic laternal sclerosis in Europe. J Neurol Neurosurg Psychiatr 2010;81:385-390

  8. Baron-Cohen S. The extreme male brain theory of autism. Trends Cogn Sci 2002;6:248-254

  9. James WH. Further evidence that some male-based neurodevelopmental disorders are associated with high intrauterine testosterone concentrations. Dev Med Child Neurol 2008;50:15-18

  10. Mouridsen SE, Hauschild KM. The sex ratio of siblings of individuals with a history of developmental language disorder. Logoped Phoniatr Vocol 2010;35:144-148

  11. Mouridsen SE, Rich B, Isager T. Sibling sex ratio of individuals diagnosed with autism spectrum disorder as children. Dev Med Child Neurol 2010;52:289-292

  12. Troisi E, Hoover RN, Thadhani R. et al. Maternal, prenatal and perinatal characteristics and first trimester maternal serum hormone concentrations. Br J Cancer 2008;99:1161-1164

  13. Maccoby EE, Doering CH, Jacklin CN et al. Concentration of sex hormones in umbilical cord blood and their relation to sex and birth order of infants. Child Dev 1979;50:632-642

  14. Vivekananda U, Johnston C, McKenna-Yasek D et al. Birth order and the genetics of amyotrophic lateral sclerosis. J Neurol 2008;255:99-102

  15. Haldane JBS, Smith CAB. A simple exact test for birth order effect. Ann Eugen (Lond)1947;14: 117-124

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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