Diminished adrenal sensitivity and ACTH efficacy in obese premenopausal women

Abstract

Background: The ACTH-cortisol axis in women is activated and associated with decreased ACTH potency, estimated by relating ACTH and cortisol pulse masses. Recently, a new accurate method for constructing the endogenous dose-response relationship was introduced, which is based on the relation between ACTH concentrations and associated cortisol secretion rates within cortisol bursts. Hypothesis: The endogenous dose-response relation between ACTH and cortisol in obesity is changed, leading to diminished responsiveness. Subjects: Twenty-five obese premenopausal women and 16 normal weight premenopausal women were studied by 10-min blood sampling for 24 h. Outcomes: ACTH and cortisol secretion rates, analytical dose-response estimates of endogenous ACTH efficacy (maximal cortisol secretion), dynamic ACTH potency, and adrenal sensitivity (slope term) from 24-h ACTH-cortisol profiles were quantified. Results: The initial potency (negative logarithm) was K7.83G0.75 (meanGS.E.M.) in obese women and K10.14G1.08 in lean women (PZ0.10), and the corresponding values for the recovery phase were K26.62G2.21 and K36.67G1.66 (PZ0.004). The sensitivity (curve slope) amounted to 0.468G0.05 in obese women and 0.784G0.09 in normal weight women (PZ0.004). The efficacy (maximal value) was 17.6G4.9 nmol/l per min in obese women and 26.3G3.8 nmol/l per min in normal weight women (PZ0.009). Basal secretion rate, inflection point, and EC 50 values were not different. Bromocriptine or acipimox did not change the dose-response curve. Conclusion: The ACTH-cortisol relation in obesity in women is characterized by decreased sensitivity and efficacy, thus explaining non-elevated serum cortisol concentrations despite increased plasma ACTH levels.

Age-Dependent and Gender-Dependent Regulation of Hypothalamic-Adrenocorticotropic-Adrenal Axis

“…↓ deep sleep and amplitude of 24-hour cortisol rhythm with age (men) 58,192  h. Abdominal visceral adiposity in older women   i. ↓ estimated ACTH efficacy 231  i. Psychosocial stress   i. ↓ ACTH increment after DEX/CRH in older (vs young) men 22  j. Mineralocorticoid agonist (9a-fludrocortisone)   i.…”

Changes in pituitary function with ageing and implications for patient care

“…42,43 Intra-abdominal adipose tissue mass is a major confounder of ACTH and/or cortisol output with high intra-abdominal adipose tissue mass predicting increased sympathetic outflow, cortisol production and cortisol inactivation, and (in women) increased mean ACTH concentrations. 42,44,45 …”

Obesity and the dysregulation of fatty acid metabolism: implications for healthy aging

“…It has been shown the HPA axis becomes increasingly hyperresponsive as a result of this metabolic change in middle-aged women [87]. Moreover, Roelfsema et al (2012) observed that basal; pulsatile; and total ACTH secretion was 1.4, 1.6, and 1.5 times greater, respectively, in obese preme-nopausal women, when compared to their normal-weight counterparts. However, despite this increase in ACTH secretion, cortisol levels remained unaffected.…”

“…However, despite this increase in ACTH secretion, cortisol levels remained unaffected. This is thought to be due to the significant decline in sensitivity to ACTH, in addition to a decrease in this hormone's efficacy [88]. Although it has been repeatedly observed that plasma cortisol is not elevated in obese individuals, there is a greater generation of cortisol within the adipose tissue, in addition to a rise in cortisol metabolite excretion [87][88][89].…”

“…This is thought to be due to the significant decline in sensitivity to ACTH, in addition to a decrease in this hormone's efficacy [88]. Although it has been repeatedly observed that plasma cortisol is not elevated in obese individuals, there is a greater generation of cortisol within the adipose tissue, in addition to a rise in cortisol metabolite excretion [87][88][89]. This may be due to 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a bidirec-tional enzyme, which acts as a reductase to convert cortisone to cortisol, and as a hydrolase for the reverse reaction [90].…”