Hum. Reprod. Advance Access published online on October 23, 2008
Human Reproduction, doi:10.1093/humrep/den370
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Letter to the Editor |
The sex ratio of offspring of women with congenital adrenal hyperplasia
The Galton Laboratory, Department of Genetics, Evolution and Environment, University College London, Wolfson House, 4 Stephenson Way, London NW1 2 HE, UK
1 Correspondence address. E-mail: whjames{at}waitrose.com
Hagenfeldt et al. (2008)
reported that the offspring born to their sample of women with congenital adrenal hyperplasia (CAH) numbered 6 boys and 19 girls. This sex ratio (proportion males) was significantly lower than that of offspring of a control sample. The authors remarked that this result was unexpected. To explore the point further, I examined the sex ratios in the papers cited by these authors. (In parenthesis, it should be noted that these are extremely rare data: attempts to extract further such data using Medline proved fruitless.) Table I here gives these data. The pooled set of fresh data is also significantly different from the expected population live birth sex ratio of contemporary European countries of 0.513. So there can be no reasonable doubt that pregnant CAH women reportedly produce a statistically significant excess of daughters. This phenomenon stands in need of explanation.
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Classical CAH is an autosomal recessive condition causing androgen excess in cases. I have hypothesized that (in contrast with the above result) high parental levels of androgens around the time of conception are associated with subsequent births of boys (James, 1996
, 2004, 2008). However, an explanation may be offered for the reported statistically significant excess of girls among the offspring of CAH mothers. It is that prior to conception in CAH women, most have been treated to suppress the androgens. This is acknowledged by all authors cited here. For instance, Hagenfeldt et al. (2008) noted such treatment variously consisting in increases in glucocorticosteroid dose, or addition of fludrocortisone, or infertility treatment, or gonadotrophin treatment or corticosteroid doses with metformin. In this context, it should be noted that the reported sex ratio of children following the induction of ovulation with gonadotrophins or clomiphene is low (James, 1985a). That result was highly significant (P < 10–6, tested against an expected contemporaneous live birth sex ratio of 0.514 in the USA). It was apparently not due to any association between offspring sex ratio and maternal subfertility: this may be inferred from the report that the sex ratio of artificial insemination offspring is also significantly lower if ovulation is hormonally induced than if ovulation occurs naturally (James, 1985b). Accordingly, I suggest that the excess of daughters born to CAH mothers is due to the hormonal treatment of these women prior to conception (which was designed to lower their formerly high androgen concentrations to below-average levels, and which may also have raised their gonadotrophin concentrations). Ex hypothesi either of these changes to the hormone profile would be responsible for the excess of daughters.
References
Dumic M, Janjanin N, Ille J, Zunec R, Spehar A, Zlopasa G, Francetic I, New MI. Pregnancy outcomes in women with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Pediatr Endocrinol Metab (2005) 18:887–895.[Web of Science][Medline]
Hagenfeldt K, Janson PO, Holmdahl G, Falhammar H, Filipsson H, Frisen L, Thoren M, Nordenskjold A. Fertility and pregnancy outcome in women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Hum Reprod (2008) 23:1607–1613.
Hoepffner W, Schulze E, Bennek J, Keller E, Willgerodt H. Pregnancies in patients with congenital adrenal hyperplasia with complete or almost complete impairment of 21-hydroxylase activity. Fertil Steril (2004) 81:1314–1321.[CrossRef][Web of Science][Medline]
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James WH. The sex ratio of infants born after hormonal induction of ovulation. Br J Obstet Gynaecol (1985) a 92:299–301.[Web of Science][Medline]
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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) 186:271–286.
James WH. Further evidence that mammalian sex ratios at birth are partially controlled by parental hormone levels around the time of conception. Hum Reprod (2004) 19:1250–1256.
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.
Krone N, Wachter I, Stefanidou M, Roscher AA, Schwarz HP. Mothers with congenital adrenal hyperplasia and their children: outcome of pregnancy, birth and childhood. Clin Endocrinol (2001) 55:523–529.[CrossRef][Medline]
Lo JC, Schwitzgebel VM, Tyrrell JB, Fitzgerald PA, Kaplan SL, Conte FA, Grumbach MM. Normal female infants born of mothers with classic congenital hyperplasia due to 21-hydroxylase deficiency. J Clin Endocr Metab (1999) 84:930–936.
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