Department of Surgery, Physiology and Bioengineering, Mayo Clinic College of Medicine, Rochester, Minnesota
ABSTRACT
This essay examines the historical significance of an APS classic paper that is freely available online: Critchlow V, Liebelt RA, Bar-Sela M, Mountcastle W, and Lipscomb HS. Sex difference in resting pituitary-adrenal function in the rat. Am J Physiol 205: 807815, 1963 (http://ajplegacy.physiology.org/cgi/reprint/205/5/807).
However, in 1963 there were no political directives to investigate sex-based differences in physiology when Critchlow and colleagues (2) performed a rigorous series of experiments directed at resolving a controversy of whether or not there were differences in pituitary-adrenal function between male and female animals under resting conditions (Fig. 1). These investigators were driven by an innate curiosity to understand differences in findings from various laboratories regarding adrenal function in male and female animals. A greater adrenal cortical secretory response to stressors in female compared with male animals was a well-documented finding from several laboratories (3, 5, 8) and not under dispute. However, the difference in adrenal cortical function between male and female animals under resting conditions was not a consistent finding, and some evidence suggested that anesthetics normalized responses between the sexes (3). To resolve these controversies and to establish reliable data obtained under nonstressed or control conditions, Critchlow and colleagues undertook three series of experiments that defined the circadian pattern of corticosterone, adrenocorticotropin (ACTH), and leukocyte activation in prepubescent, sexually mature, and gonadectomized male and female rats. To validate circadian cyclicity of responses, animals were light-phase shifted or blinded, and circadian measurements were repeated. Blood was collected from each group of animals at 4-hour intervals for periods of 2432 hours either by rapid decapitation or while animals were anesthetized with pentobarbital sodium. These arduous protocols reflect the dedication and energy the young Dr. Critchlow expended in order to obtain quality data.
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Results of the Critchlow experiments provided the classic validation that the pituitary-adrenal axis is sexually dimorphic under resting (control) conditions and can be modulated both by hormonal status and by neurological processes inhibited by barbiturates. One wonders how many interesting observations are missed today because of lack of attention by investigators to the circadian patterns of activity or hormonal status of the experimental subjects. In addition, investigators often do not know the extent to which various analgesics or anesthetics required by animal regulatory panels may interact with or modulate particular physiological responses of interest.
Readers of this classic paper will immediately notice differences in the structure of that paper compared with reports of today. One obvious difference between the two groups of papers separated by almost half a century is the minimalistic statistical analysis of the data. Unlike requirements for some journals today for "independent statistical review," statistics of the Critchlow study were described with one sentence: "All statistical probabilities were derived from analysis of variance." Figures and text, unlike today's papers, were not peppered with the prerequisite asterisks, crosses, and P values to the nth decimal level of statistical significance. Differences between responses of male and female animals are obvious to the reader and as such emphasize that statistics are a tool, like other scientific assays, and statistical significance should not override common sense.
A second difference between papers of today and the Critchlow study is the lack of translational relevance or applied rationale for the study. In a recent interview with Dr. Critchlow, he indicated that his group simply needed reliable baseline information from which to design future experiments. Although their investigative team had considered possible clinical relevance of their observations, he and his colleagues were simply not aware of any. Needless to say, observations from these basic experiments have clinical relevance today. Indeed, it has taken over 40 years for sexual dimorphic responses to cortisol to be observed and validated in pubertal humans (10), and today it is recognized that estrogen-modulated release of ACTH has implications for sex disparities in incidence of depression, reproductive disorders (4), and perhaps acute stress-induced Tako-Tsubo cardiopathy (1).
By today's standards, the study by Critchlow and colleagues could perhaps be labeled "descriptive," an adjective that often pronounces a death sentence for publication of papers in so-called "high-impact" journals. Fortunately, physiologists recognize the value of definitive, descriptive, integrative experiments that provide insight into controversial findings. It is just such descriptive observations that are still cited after 40 years (9) because they provide the background information that is necessary to explore more mechanistic approaches to understanding how physiological systems are modulated.
In the 21st century world of genomics and political correctness in science, sexual genotype or sex-based differences in physiological responses coupled with definition of hormonal status of the experimental subject are important variables to consider in the development of novel preventive, diagnostic, and treatment strategies in medicine. In addition, students of physiology would do well to follow Dr. Critchlow's advice, that is, "to be curious and to have fun with the discovery process." This timeless advice overshadows political correctness and, when followed, results in classic discoveries.
FOOTNOTES
Address for reprint requests and other correspondence: V. M. Miller, Dept. of Surgery, Physiology and Bioengineering, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905 (e-mail: miller.virginia{at}mayo.edu)
REFERENCES
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