Short-term energy deprivation alters activin a and follistatin but not inhibin B levels of lean healthy women in a leptin-independent manner

Abstract

Context: Leptin is a potent modulator of the hypothalamic-pituitary-gonadal axis mediating the effect of energy deprivation on several hypothalamic-pituitary-peripheral axes. Activin A, inhibin B, and follistatin (FST) also regulate the hypothalamic-pituitary-gonadal axis in humans. It remains unknown whether energy deprivation affects these hormone levels in a leptin-dependent or -independent manner.

Objective: We investigated 1) day-night variability patterns of activin, inhibin, and FST in the fed state, 2) whether their levels are affected by fasting, and 3) whether such an effect is mediated by leptin in physiological replacement or pharmacological doses.

Design: We conducted two studies in healthy, eumenorrheic females, each comprising three separate admissions. In study 1, six women were maintained for 72 h 1) on isocaloric diet, 2) fasting while receiving placebo, or 3) fasting while receiving metreleptin in physiological replacement doses. In study 2, five women were administered physiological or pharmacological metreleptin doses (0.01, 0.1, or 0.3 mg/kg i.v. four times daily).

Results: Neither activin A nor FST had a pulsatile or day-night variability pattern. Inhibin B levels were also nonpulsatile, but a trend toward a day-night pattern was noted. When compared with the fed state, inhibin B levels remained unchanged, whereas FST levels increased (P = 0.01) and activin A decreased (P = 0.01) in the fasting state. These changes were not corrected with metreleptin administered in replacement or pharmacological doses.

Conclusions: Short-term energy deprivation alters levels of activin A and FST, but these effects are not mediated by leptin.

Trial registration: ClinicalTrials.gov NCT00140205 NCT00140231.

Figures

Fig. 1.

Average 24-h (0800–0800 h) leptin (n = 6) (A), FST (n = 6) (B), activin A (n = 6) (C), and inhibin B (n = 9) (D) levels on d 3 of baseline fed state (nonlinear adjusted R2 is displayed on top center of each panel; dashed lines represent 95% prediction band; solid lines represent 95% confidence bands).

Fig. 2.

Average (n = 6) 24-h profile (0800–0800 h) of FST (A), activin A (B), and inhibin B (C) levels on d 3 of baseline fed state (blue), 72 h fasting with placebo (red), and 72 h fasting with replacement-dose meterleptin (green) (P values are shown next to brackets, lower P values shown in italics are adjusted for age and BMI).

Fig. 3.

Average (n = 6) 24-h profile (0800–0800 h) of leptin, LH (12, 13), FSH, FST, inhibin B, and activin A levels on d 3 of baseline fed state (left), 72 h fasting with placebo (center), and 72 h fasting with replacement-dose meterleptin (right) (blue arrows indicate meals; green arrows indicate iv placebo/leptin).