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Department of Gynecology and Obstetrics Emory University School of Medicine Atlanta, Georgia 30322
Address all correspondence and requests for reprints to: Dr. Sarah L. Berga, Emory University School of Medicine, Department of Gynecology and Obstetrics, 1639 Pierce Drive, Room 4208-WMB, Atlanta, Georgia 30322. E-mail: sberga{at}emory.edu.
Stress, defined as a perturbation of the hypothalamic-pituitary-adrenal (HPA) axis, is arguably the most common cause of reproductive compromise. This tenet can be harnessed to wisely and expertly regulate fertility and safeguard reproductive health, but to do so requires an understanding of the exact mechanisms linking stress and reproductive competence. Investigative barriers stem partly from the need to define and reliably quantify stress. For practical reasons, most investigators have manipulated readily defined variables, such as caloric insufficiency and infectious agents, rather than psychogenic variables, to interrogate this interaction. An unintended consequence of this experimental approach has been to dichotomize stressors into those deemed metabolic (and quantifiable) vs. those viewed as psychogenic or psychosocial (and not as readily quantified). Perhaps owing to the lack of ready measurement, some investigators have dismissed the relevance of psychogenic factors by arguing that psychogenic stress in the absence of undernutrition rarely disrupts reproduction. Is the dichotomization into metabolic vs. psychogenic silos valid? It would be valid if undernutrition failed to activate the neural machinery subserving the transduction of stress signals, that is, if conditions that created a negative energy balance did not activate the HPA axis and thus were not bona fide stressors. The study by Vulliemoz et al. (1) in this issue of Endocrinology addresses this controversy by showing that blockade of CRH, using the CRH antagonist astressin B, reversed the reproductive compromise initiated by negative energy balance. In effect, their results validate the notion that undernutrition is a stressor in a classical sense. Furthermore, the investigators reinforce the perspective that activation of the HPA axis causally links stress and reproduction compromise. One might consider this study to represent an epistemological, as opposed to molecular, knockout. Accordingly, we should dismiss as false dichotomy the view that stressors are either metabolic or psychogenic. Any behavior or agent that activates the stress signaling system can serve as a stressor with both psychogenic and metabolic faces. Despite the semantic convenience, the two are largely inseparable, both behaviorally and pathophysiologically. Thus, metabolic and psychogenic stressors might well be viewed as the two sides of a coin rather than independent silos. Before the advent of neuroimaging, it was possible to think of thought as devoid of metabolic activation, but we now know that thoughts and feelings activate the most metabolically active tissue in the body, namely, the brain. Thus, stressful thoughts carry an independent energy burden in addition to that which accompanies the hormonal cascade or behavior so triggered.
The study design employed by Vulliemoz et al. (1) cleverly used ghrelin to induce negative energy balance and was based on previous studies in female rhesus monkeys showing that the administration of ghrelin, a key driver of appetite and energy homeostasis, suppressed LH pulse frequency, itself a surrogate for central GnRH drive, while concomitantly elevating cortisol levels, a marker of HPA activation. In the current paradigm, monkeys were given an infusion of either astressin B or saline before the administration of ghrelin. LH pulse frequency remained unchanged after saline infusion with or without astressin B. Ghrelin reduced LH pulse frequency and stimulated cortisol secretion, but prior infusion of astressin B prevented the decrease in LH and the rise in cortisol. Previous research in this area never directly hit the nail on the head. For instance, Loucks et al. (2) showed that a graded energy deficiency given to eumenorrheic women could, when extreme, suppress LH drive and that this suppression was accompanied by a commensurate increase in cortisol. We have shown that applying metabolic and psychogenic stressors independently to cynomolgus monkeys rarely interrupts menstrual cyclicity and ovarian steroid hormone production, whereas combining the same stressors profoundly suppresses reproductive function (3). Metabolic and psychosocial stressors seem to interact synergistically to disrupt reproductive competence. Thus, a seemingly minor psychosocial stressor, when coupled with another seemingly small metabolic challenge, induces a much larger pathophysiological impact than would be otherwise expected. However, neither of these paradigms determined whether there was concomitant CRH activation. Even direct measurement of CRH and cortisol in the cerebrospinal fluid of women with functional hypothalamic amenorrhea was able to only indirectly implicate CRH as a mediator of reproductive compromise (4). Thus, the study by Vulliemoz et al. (1) is a true step forward in our understanding of the mechanisms by which energy balance gates reproductive competence.
One may well ask why it matters to understand the impact of stress and types of stressors upon reproduction. A major dividend is in the care of patients. By avoiding false dichotomies, we can provide better, more nuanced, clinical care. If calories alone were the treatment for reproductive compromise due to undernutrition, then the answer would be to eat more. It is commonplace to recommend to infertility patients, especially women with so-called unexplained infertility, that they eat more and gain weight. However, patients who are stressed rarely resonate with this recommendation. Why? The short answer is that their drive to eat is reduced and the thought of increasing food intake is unpalatable. If stress itself reduces appetite, then mandating more caloric intake will not necessarily translate into action. As anyone who has cared for anorectic cancer patients has observed, it is difficult to eat when one is not in full possession of appetite. The converse holds, too. Although it is hard to eat when not hungry, it is harder yet to not eat when hungry. Does stress gate appetite? The simple answer is yes, but the gating mechanisms are not so simple. It appears that the more profound the stress, the less the appetite. A little stress may well engender a mild compensatory increase in appetite, but a lot of stress appears to cause anorexia even in the face of enhanced orexigenic signaling (5). For some reason, despite the apparent importance of understanding appetite and the availability of powerful tools for dissecting the neurobiological mechanisms, including neuroimaging during stimulus presentation, this topic has received minimal investigative attention. Those of us who are daily confronted with a varied spectrum of clinical presentations involving weight, diet, and reproductive failure have a strong drive to know more about how to regulate eating behavior so as to help those who are obese to not eat and those who are lean or stressed to eat more appropriately. Appetite thus stands as an important integrating signal for understanding the impact of stressors upon reproductive competence.
In daily living, metabolic and psychogenic behaviors are rarely separate. If stress reduces appetite, then could stress reduction restore appetite and shift energy balance from negative to positive? To the best of my knowledge, a direct test of this notion has never been undertaken, but an ideal population in which to test it would be women with stress-induced anovulation, often termed functional hypothalamic amenorrhea. We were able to show that stress reduction effected using cognitive techniques restored ovarian function and menstrual cyclicity in women with functional hypothalamic amenorrhea (6), but we did not measure energy balance. Thus, the concept remains relatively unexplored. For the moment, available data suggest that negative energy balance is a stressor regardless of the behavior or circumstance engendering negative energy balance. Previous HPA axis activation, whether by a predominantly psychogenic or metabolic behavior, sensitizes the reproductive axis to the next stressor, making its impact disproportionately large (3, 7). Understanding the impact upon neural machinery of previous HPA activation may explain why multiple small stressors are synergistic rather than additive. To buttress the system and facilitate recovery through behavioral techniques, it might well prove useful to concomitantly desensitize the HPA axis using a CRH antagonist. It remains to be seen whether CRH antagonist exposure would restore sensitivity to endogenous or exogenous orexigenic signals and thus buttress the reproductive system from the insults of subsequent stressors by increasing suboptimal appetite while coping techniques to reduce sensitivity to psychogenic stressors are mastered.
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Abbreviation: HPA, Hypothalamic-pituitary-adrenal.
Received January 3, 2008.
Accepted for publication January 4, 2008.
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