Conditioned hormonal responses: A systematic review in animals and humans.
Topic: Hormone Therapy

In contrast to classical conditioning of physiological responses such as immune responses and drug effects, only a limited number of studies investigated classical conditioning of endocrine responses. The present paper is the first systematic review that integrates evidence from animal and human trials regarding the possibility to condition the endocrine responses. Twenty-six animal and eight human studies were included in the review. We demonstrated that there is accumulating evidence that classical conditioning processes are able to influence specific endocrine responses, such as cortocosterone/cortisol and insulin, while more limited evidence exists for other hormones. Animal and human studies were generally consistent in their findings; however, the limited number of human studies makes it difficult to generalize and translate the results of animal research to humans. Next to methodological recommendations for future studies, we suggest several ways how classically conditioned endocrine responses can be used in clinical practice.

PICO
Population: Animals and humans
Intervention: Classical conditioning of endocrine responses
Comparison: No specific comparison group mentioned
Outcomes: Influence on specific endocrine responses such as cortocosterone/cortisol and insulin, potential clinical applications

Included studies:
title: Classical conditioning and conditionability of insulin and glucose effects in healthy humans.
abstract: We examined whether the effects of intravenously injected insulin and glucose (the physiological endogenous insulin production stimulus) could be classically conditioned in healthy humans. We expected a conditioned blood glucose decrease to a conditioned stimulus (CS) previously paired with insulin and an, albeit lower, blood glucose decrease to a CS paired with glucose injection. In addition, we analyzed glucoregulatory hormone and symptom conditionability. Thirty healthy males were divided into three groups and were given the CS and an intravenous injection of either insulin (0.05 IU/kg) in Group 1, glucose (15%, 0.5 g/kg) in Group 2, or placebo [physiological saline (0.9%)] in Group 3 during the acquisition phase on 4 days. All participants were given the olfactory CS (rosewood-peppermint smell) and placebo injection on Day 5 (test). On Day 5, the total blood glucose decrease tended to be higher in Group 1 than in Group 3 (P<.10), especially at CS presentation (P<.10) and previous unconditioned hypoglycemia time-point (P<.05). The conditioned blood glucose decrease was statistically nonsignificant in Group 2, but shortly after CS presentation, insulin level and blood glucose changes were negatively correlated in Groups 1 and 2 in contrast to positive correlation in Group 3. Furthermore, Group 1 showed an increase in noradrenaline (P<.05), a temporarily delayed increase in growth hormone (GH; P<.05), and an increase of autonomic and neuroglycopenic symptoms, reaching a medium and small effect size, respectively. Group 2 responded with an increase in cortisol (P<.01) and neuroglycopenic symptoms (P<.05) at the time-point of the previous unconditioned blood glucose minimum. To conclude, the effects of exogenously applied insulin can be conditioned in a reliable way. In correspondence with the lower intensity of the unconditioned stimulus (US), conditioning effects with glucose-and, thus, endogenously produced insulin-are weaker but also reflect the actions of central insulin. Future studies will examine the diverse actions of insulin within the brain further.
title: Effects of overshadowing on conditioned nausea in cancer patients: an experimental study.
abstract: The infusion of cytotoxic drugs in cancer patients is often accompanied by posttreatment nausea (PN). In addition, patients complain about nausea prior to an infusion [i.e., anticipatory nausea (AN)]. AN is mainly explained by classical conditioning, with the infusion as the unconditioned stimulus (US) and with the stimuli signaling the infusion as conditioned stimuli (CS). Despite this conditioning etiology, a specifically derived therapy to attenuate the CS-US contingency is missing. The purpose of this study is to develop and to test an overshadowing procedure for prevention of AN, and also for the modification of PN intensity. Sixteen cancer patients were assigned to one of two groups: Overshadowing+ (OV+) and Overshadowing- (OV-). At the start of all infusions of two consecutive chemotherapy cycles A and B (acquisition), OV+ subjects drank a saliently tasting beverage (the overshadowing CS), whereas group OV- drank water. All patients received water in cycle C (test). Self-reported symptoms and heart rates were recorded. As expected, in cycle C (test), no patient of group OV+ showed AN, whereas two patients of group OV- developed AN. There was a tendency for a reduction of the intensity of PN, in terms of duration and latency after overshadowing, in cycle C: OV+ patients tended to show a shorter duration and a longer latency between end of infusion and PN onset. In OV-, there was a significantly larger heart rate deceleration in both measurement periods, in the anticipatory and the posttreatment measurement period. Data suggest to apply overshadowing for prevention of AN and modification of PN. Physiological markers of conditioned nausea are revealed. After its procedural implementation, the technique can be used in larger samples now.
title: Conscious expectation and unconscious conditioning in analgesic, motor, and hormonal placebo/nocebo responses.
abstract: The placebo and nocebo effect is believed to be mediated by both cognitive and conditioning mechanisms, although little is known about their role in different circumstances. In this study, we first analyzed the effects of opposing verbal suggestions on experimental ischemic arm pain in healthy volunteers and on motor performance in Parkinsonian patients and found that verbally induced expectations of analgesia/hyperalgesia and motor improvement/worsening antagonized completely the effects of a conditioning procedure. We also measured the effects of opposing verbal suggestions on hormonal secretion and found that verbally induced expectations of increase/decrease of growth hormone (GH) and cortisol did not have any effect on the secretion of these hormones. However, if a preconditioning was performed with sumatriptan, a 5-HT(1B/1D) agonist that stimulates GH and inhibits cortisol secretion, a significant increase of GH and decrease of cortisol plasma concentrations were found after placebo administration, although opposite verbal suggestions were given. These findings indicate that verbally induced expectations have no effect on hormonal secretion, whereas they affect pain and motor performance. This suggests that placebo responses are mediated by conditioning when unconscious physiological functions such as hormonal secretion are involved, whereas they are mediated by expectation when conscious physiological processes such as pain and motor performance come into play, even though a conditioning procedure is performed.
title: Effects of physical activity on risk factors for coronary heart disease in previously sedentary women: a five-year longitudinal study.
abstract: Fitness, weight, blood-pressure, and lipids were measured in 290 women joining a fitness programme. Five years later, 110 (38%) had remained active, and the others had become sedentary again. The net effect of being active was to increase fitness by 18% and to reduce weight by 1.9 kg, diastolic blood pressure by 3 mmHg, and triglycerides by 0.15 mmol/L-1. After controlling for age, weight and fitness, physical activity accounted for 1% and 3% of the variance of changes in systolic and diastolic blood pressure respectively, and was not associated with changes in lipids. Change in fitness accounted for only 1% of change in diastolic blood pressure. More 'active' women gave up smoking than 'inactive' (70% versus 10%). Hypertensive women were more sensitive to changes in weight and fitness than normotensive women. It was concluded that physical activity and change in fitness were only weakly related to changes in blood pressure and were unrelated to changes in lipids.
title: Conditioned pharmacotherapeutic effects: a preliminary study.
abstract: To test the hypothesize that psoriasis patients treated under a partial schedule of pharmacologic (corticosteroid) reinforcement would show less severe symptoms and relapse than those given the same amount of drug under standard conditions. Behavioral conditioning as an inherent component of many pharmacotherapeutic protocols has never been examined.
title: Classical conditioning of insulin effects in healthy humans.
abstract: Classical conditioning of insulin effects was examined in healthy humans using a placebo-controlled design. This study examined whether subjects who experienced a conditioned stimulus (CS) paired with insulin in the acquisition phase of a conditioning protocol would show a conditioned decrease of blood glucose when receiving the CS with a placebo injection in the test phase.
title: Latent inhibition of rotation chair-induced nausea in healthy male and female volunteers.
abstract: Pre-exposure to an environment in which a nausea-inducing body rotation will subsequently be given constitutes a latent inhibition procedure that might act to reduce anticipatory and postrotation nausea.
title: Conditioning rhinitis in allergic humans.
abstract: A classical Pavlovian paradigm pairing an olfactory cue with allergen challenge for a single training trial was used to produce conditioned histamine release and conditioned nasal airflow decrease in seasonal allergic rhinitis sufferers. There was no conditioned increase in subjective symptoms. Histamine release and airflow decrease showed evidence of extinction by a second test trial. A second study comparing the effects of the number of training trials showed that three training trials produced greater histamine release and airflow decrease than a single training trial, suggesting stronger effects with additional training.
title: Unconditioned and conditioned effects of intranasally administered insulin vs placebo in healthy men: a randomised controlled trial.
abstract: In humans, the intranasal route allows insulin to reach the brain while maintaining peripheral euglycaemia. Our aims were to examine acute (unconditioned) effects of central insulin on normal-range blood glucose and hormones in men, and to find out whether the effects of intranasal insulin can be learnt via classical conditioning.
title: Plasma cortisol response cannot be classically conditioned in a taste-endocrine paradigm in humans.
abstract: Peripheral immune responses can be modified by associative learning procedures. Less is known, however, whether and to what extent neuroendocrine parameters can be classically conditioned.
title: Pavlovian conditioning of taste aversion using a motion sickness paradigm.
abstract: Pavlovian conditioning of taste aversion has rarely been investigated in healthy humans using motion sickness as the unconditioned stimulus (US).
title: Classically conditioned changes in plasma cortisol levels induced by dexamethasone in healthy men.
abstract: Animal research has indicated that the activity of the hypothalamic-pituitary-adrenal axis can be influenced by classical (Pavlovian) conditioning procedures. To test the hypothesis that alterations in plasma cortisol levels can be conditioned in humans, the present study used a prospective, randomized, double-blind, placebo-controlled design in which a distinctively flavored beverage was paired with p.o. administration of dexamethasone. Twenty-five healthy men were randomly assigned to one of two groups. During the conditioning phase of the study, subjects in the experimental group received three conditioning trials (pairings of a distinctively flavored beverage with a capsule containing 5 mg dexamethasone) separated by 1 wk recovery periods. Subjects in the control group were treated identically, except that the capsule contained a placebo. During the test phase, all subjects underwent a test day (reexposure to the distinctively flavored beverage before receiving a placebo capsule) and a comparison day (no exposure to the beverage or the capsule). Plasma cortisol was assessed repetitively before and after administration of the beverage and capsule, as were possible confounding factors, including: behavioral variables, psychological distress, aversive reactions to the beverage, and expectations of treatment. After reexposure to the beverage and administration of a placebo capsule (conditioned stimuli), the experimental group had significantly higher levels of plasma cortisol than the control group, after controlling for variability in baseline levels of cortisol (F(5,60)=3.09; P=0.015) that could not be explained by differences in other study variables. No differences in cortisol levels were found on the comparison day. These results support the study hypothesis that changes in plasma cortisol levels can be classically conditioned in humans by pairing a distinctive beverage with p.o. administration of dexamethasone.
title: Massive resection of the liver following blunt trauma.