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Is there a gender difference in the associations of birthweight and adult hypothalamic–pituitary–adrenal axis activity?

Endocrinology Unit, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK, ¹ Medical Research Council Environmental Epidemiology Unit, University of Southampton, Southampton, UK and ² Regional Endocrine Unit, Southampton General Hospital, Southampton, UK

(Correspondence should be addressed to R M Reynolds; Email: r.reynolds{at}ed.ac.uk)

Objective: Increased hypothalamic–pituitary–adrenal (HPA) axis activity in men of low birthweight may be an important link between early life and the adult metabolic syndrome. In animal models females are more sensitive than males to HPA axis programming, but whether gender influences susceptibility in humans is unknown.

Design: Birth cohort study.

Methods: We studied 106 women aged 67–78 years, from Hertfordshire, UK, in whom birthweight was recorded. Negative feedback sensitivity was assessed by an overnight low-dose (0.25 mg) dexa-methasone suppression test, and adrenal sensitivity by a low-dose (1 µg) ACTH_{1 – 24} stimulation test. Cortisol and its metabolites were analysed in a 24 h urine collection. Data were compared with previously published identical measurements in 205 men aged 66–77 years from the same cohort.

Results: In women, plasma cortisol levels after dexamethasone were lower (P < 0.0001) and peak cortisol following ACTH_{1 – 24} were higher (P < 0.0001) than in men, suggesting a more responsive HPA axis. As in men, women with lower birthweight had enhanced plasma cortisol responses to ACTH_{1 – 24} (P = 0.05 for trend) but no difference in plasma cortisol after dexamethasone or in urinary cortisol metabolite excretion. The strength of the association in women was not different from that in men; a 1 lb decrease in birthweight was associated with an incremental rise in cortisol of 12.6 nmol/l (95% confidence interval (CI) 1.4, 23.8) in men, P = 0.03, and 14.8 nmol/l (95% CI –0.4, 29.9) in women, P = 0.05 (P = 0.82 for birthweight x gender interaction). In a combined analysis of men and women adjusted for gender (n = 302), a 1 lb decrease in birthweight was associated with a 13.4 nmol/l (95% CI 4.5, 22.4) greater incremental rise in plasma cortisol, P = 0.003.

Conclusions: Associations between lower birthweight and increased HPA axis activity are similar in men and women, supporting the hypothesis that HPA axis activation is an important mechanism underlying programming of adult disease.

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