Submitted on June 13, 2007
Accepted on August 31, 2007
A Noninvasive Measure of Negative-Feedback Strength, Approximate Entropy, Unmasks Strong Diurnal Variations in the Regularity of Luteinizing Hormone Secretion
Peter Y. Liu1, Ali Iranmanesh2, Daniel M. Keenan3, Steven M. Pincus4, and Johannes D. Veldhuis5*
1 Andrology, ANZAC Research Institute, Sydney, New South Wales, Australia
2 Endocrine Service, Research and Development, Salem Veterans Affairs Medical Center, Salem, Virginia, United States
3 Department of Statistics, University of Virginia, Charlottesville, Virginia, United States
4 Guilford, Connecticut, United States; 990 Moose Hill Road, Guilford,, Connecticut, 6437, United States
5 of Internal Medicine, Gen. Clinical Res. Ctr, Mayo Medical and Graduate Schools of Medicine, Rochester, Minnesota, United States
* To whom correspondence should be addressed. E-mail: veldhuis.johannes{at}mayo.edu.
The secretion of anterior-pituitary hormones is subject to negative feedback. Whether negative feedback evolves dynamically over 24 hr is not known. Conventional experimental paradigms to test this concept may induce artefacts due to nonphysiological feedback. These limitations might be overcome by a noninvasive methodology to quantify negative feedback continuously over 24 hr without disrupting the axis. The present study exploits a recently validated model-free regularity statistic, approximate entropy (ApEn), which monitors feedback changes with high sensitivity and specificity (both > 90%) [Am J Physiol 273: E948-57, 1999]. A time-incremented moving window of ApEn was applied to LH time series obtained by intensive (10-min) blood sampling for 4 consecutive days (577 successive measurements) in each of 8 healthy men. Analyses unveiled marked 24-hr variations in ApEn with daily maxima (lowest feedback) at 1100 ± 1.7 hr (mean ± SEM) and minima (highest feedback) at 0430 ± 1.9 hr. The mean difference between maximal and minimal 24-hr LH ApEn was 0.348 ± 0.018, which differed by P < 0.001 from all 3 of randomly shuffled versions of the same LH time series, simulated pulsatile data and assay noise. Analyses artificially limited to 24-hr rather than 96-hr data yielded reproducibility coefficients of 3.7-9.0% for ApEn maxima and minima. In conclusion, a feedback-sensitive regularity statistic unmasks strong and consistent 24-hr rhythmicity of the orderliness of unperturbed pituitary-hormone secretion. These outcomes suggest that ApEn may have general utility in probing dynamic mechanisms mediating feedback in other endocrine systems.
