Distinct and Convergent Beneficial Effects of Estrogen and Insulin on Cognitive Function in Healthy Young Men.

CONTEXT: Systematic investigations into the cognitive impact of estradiol and insulin in male individuals are sparse, and it is unclear whether the 2 hormones interact to benefit specific cognitive functions in humans. OBJECTIVE: We investigated the acute effect of estradiol and insulin and of their combined administration on divergent (creative) and convergent (arithmetical) thinking as well as short-term and working verbal memory in healthy young men. METHODS: According to a 2 × 2 design, 2 groups of men (each n = 16) received a 3-day transdermal estradiol (100 µg/24 h) or placebo pretreatment and on 2 separate mornings were intranasally administered 160 IU regular human insulin and, respectively, placebo before completing a battery of cognitive tests; we also determined relevant blood parameters. RESULTS: Estrogen compared with placebo treatment induced a 3.5-fold increase in serum estradiol and suppressed serum testosterone concentrations by 70%. Estrogen in comparison to placebo improved creative performance, that is, verbal fluency and flexibility, but not arithmetical thinking, as well as verbal short-term memory, but not visuospatial memory. The combination of estrogen and insulin enhanced recognition discriminability at delayed verbal memory recall; insulin alone remained without effect. CONCLUSION: Estrogen specifically enhances core aspects of creativity and verbal memory in young male individuals; delayed recognition memory benefits from the combined administration of estradiol and insulin. Our results indicate that insulin's acute cognitive impact in young men is limited and not robustly potentiated by estradiol. Estradiol per se exerts a beneficial acute effect on creative and verbal performance in healthy young men.

Insulin and Estrogen Independently and Differentially Reduce Macronutrient Intake in Healthy Men.

Context: Insulin administration to the central nervous system inhibits food intake, but this effect has been found to be less pronounced in female compared with male organisms. This sex-specific pattern has been suggested to arise from a modulating influence of estrogen signaling on the insulin effect. Objective: We assessed in healthy young men whether pretreatment with transdermal estradiol interacts with the hypophagic effect of central nervous insulin administration via the intranasal pathway. Design, Setting, Participants, and Intervention: According to a 2×2 design, two groups of men (n = 16 in each group) received a 3-day transdermal estradiol (100 µg/24 h) or placebo pretreatment and on two separate mornings were intranasally administered 160 IU regular human insulin or placebo. Main Outcome Measures: We assessed free-choice ad libitum calorie intake from a rich breakfast buffet and relevant blood parameters in samples collected before and after breakfast. Results: Estrogen treatment induced a 3.5-fold increase in serum estradiol concentrations and suppressed serum testosterone concentrations by 70%. Independent of estradiol administration, intranasal insulin reduced the intake of carbohydrates during breakfast, attenuating in particular the consumption of sweet, palatable foods. Estradiol treatment per se decreased protein consumption. We did not find indicators of eating-related interactions between both hormones. Conclusions: Results indicate that, in an acute setting, estrogen does not interact with central nervous insulin signaling in the control of eating behavior in healthy men. Insulin and estradiol rather exert independent inhibiting effects on macronutrient intake.

Comparable sensitivity of postmenopausal and young women to the effects of intranasal insulin on food intake and working memory.

CONTEXT: We have previously shown that enhancing brain insulin signaling by intranasal administration of a single dose of the hormone acutely reduces food intake in young men but not women, whereas its improving effects on spatial and working memory are restricted to young women. OBJECTIVE: Against the background of animal studies suggesting that low estrogen concentrations are a prerequisite for the anorexigenic impact of central nervous insulin, we extended our foregoing study by assessing intranasal insulin effects in postmenopausal women with comparatively low estrogen concentrations, expecting them to be more sensitive than young women to the anorexigenic effects of the hormone. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTION: In a within-subject, double-blind comparison performed at the University of Lübeck, 14 healthy postmenopausal women (body mass index, 23.71±0.6 kg/m2; age, 57.61±1.14 yr) were intranasally administered 160 IU regular human insulin or vehicle. MAIN OUTCOME MEASURES: Subjects performed a working memory task (digit span) and a hippocampus-dependent visuospatial memory task. Subsequently, free-choice food intake from an ad libitum breakfast buffet was measured. RESULTS: Contrary to expectations, results in postmenopausal women mirrored those found in young women (22.44±0.63 yr), i.e. insulin administration did not affect food intake (P>0.46), but did enhance performance in the prefrontal cortex-dependent working memory task (P<0.05). CONCLUSIONS: Low estrogen levels as present in postmenopausal women do not modulate the effects of intranasal insulin in females, suggesting that in humans as opposed to rats, estrogen signaling does not critically alter central nervous system sensitivity to the effects of insulin on energy homeostasis and cognition.

A 3-day estrogen treatment improves prefrontal cortex-dependent cognitive function in postmenopausal women.

Estrogen secretion in young women follows a cyclic pattern characterized by a pronounced surge in estrogen around ovulation. The way in which this estrogen peak affects cognitive functioning is unclear. Short-term estrogen treatment for a few days mimicking normal pre-menopausal estrogen dynamics substantially enhanced cognitive functions in ovariectomized animals. Here, we provide evidence that inducing a single estrogen peak in postmenopausal women improves their cognitive abilities. Healthy women (51-64 yrs, n=14) received either 100 microg estrogen transdermally for 3 days or placebo in a double-blind within-subject design. The treatment caused a temporary rise in serum estrogen levels roughly comparable to the mid-cyclic changes in estrogen in young women. At the end of the treatment, the women completed two types of tests involving primarily hippocampus-dependent functions of memory retention or prefrontal cortex-dependent functions. Results revealed a clear beneficial effect of estrogen on tasks mainly involving the prefrontal cortex: performance on a digit-ordering task (p<0.05) and on a task requiring short-term memory of event sequences in an unfamiliar story (p<0.01) were improved, and susceptibility to interference in the Stroop test (p<0.05) was diminished after estrogen. On the other hand, estrogen did not affect hippocampus-dependent retention of a story, with delayed recall tested after 30 min or 1 week, although immediate recall was improved by estrogen. We conclude that in postmenopausal women, a transient increase in plasma estrogen concentration acutely improves prefrontal cortex-dependent cognitive functions, whereas hippocampus-dependent memory retention is less affected. Our results encourage future studies to investigate whether repeated induction of short-lasting estrogen peaks could enhance cognitive efficacy of hormonal replacement therapy.

Acute influences of estrogen and testosterone on divergent and convergent thinking in postmenopausal women.

Previous studies indicated an enhanced capability of divergent creative thinking in young women during the ovulatory phase, which expressed itself also by an increased dimensional complexity of ongoing electroencephalographic (EEG) activity. Considering the enhanced plasma levels of estrogen and testosterone characterizing the ovulatory phase, we tested whether short-term administration of estrogen or testosterone in postmenopausal women with constantly low levels of gonadal steroids induces similar changes in divergent thinking. In two placebo-controlled cross-over studies, healthy postmenopausal women (n=12, in each study, mean age 58 years, range 47-65 years) were treated transdermally over 3 days with estrogen and testosterone, respectively, at doses inducing plasma hormone concentrations comparable with those observed in young women around ovulation. Capabilities of divergent thought and convergent analytical thought, performance on motor perseveration, and verbal memory were examined. EEG activity was recorded while subjects performed on tasks of thinking and during mental relaxation. Estrogen impaired divergent thinking (p <0.01) and enhanced convergent thinking, motor perseveration, and memory for the initial word list (p <0.05 for all tests). In parallel, EEG dimensional complexity was reduced (p <0.05). Overall, these changes indicate an estrogen-induced shift from a "divergent" towards a more "convergent" mode of processing. However, overall less consistent, effects of testosterone were opposite to those of estrogen. It increased performance on some of the divergent thinking tasks (p <0.05), and tended to increase EEG dimensional complexity during divergent thinking. Data indicate a differential sensitivity of modes of thinking to short-term treatment with estrogen and testosterone in postmenopausal women.

Food deprivation fails to affect preoccupation with thoughts of food in anorectic patients.

OBJECTIVES: Memory for food words was used to investigate effects of hunger and satiety on information processing in acute and recovered anorectics. DESIGN: In Expt 1, recall of words related to food and unrelated to food was compared between anorectics and controls. In Expt 2, the same procedure was undertaken in recovered anorectics and controls. METHODS: Tests were performed in each subject after starvation and after food intake. RESULTS: When hungry, recall of food words did not differ between anorectics and controls. During satiety, however, anorectics recalled significantly more food words than controls. Recall of food unrelated words did not differ between both groups. Recall in recovered anorectics was comparable with that in acute anorectics. CONCLUSIONS: Results indicate that cognitive processing of food stimuli does not depend on food deprivation in anorectics.