Objective: Results from animal and human studies suggest that disregulations of the hypothalamus-pituitary-adrenal (HPA) axis are involved in several behavioral, circulatory, endocrine, and immune disorders with clear-cut gender differences in disease prevalence. The aim of the present study was to investigate sex-specific HPA response patterns with a focus on the contribution of gonadal steroids as possible mediators. Methods: A total of 81 healthy adults were investigated in the present study. Twenty men, 19 women in the follicular phase of the menstrual cycle, 21 women in the luteal phase, and 21 women using oral contraceptives (OC) were exposed to a brief psychosocial stress test (Trier Social Stress Test; TSST) and injected with 0.25 mg ACTH 1‐24 on consecutive days. Basal HPA activity was investigated by repeatedly measuring cortisol levels immediately after awakening, as well as in 30-minute intervals from 9:00 AM to 9:00 PM. Additionally, questionnaires were used to assess psychological state and trait parameters. Results: Results show that the TSST induced significant increases in ACTH, salivary-free cortisol, total plasma cortisol, and heart rates, as well as increased wakefulness and reduced calmness in the total group. Significant group differences emerged for ACTH and salivary-free cortisol stress responses: Although men showed higher ACTH responses to the TSST compared with each of the three groups of women, salivary cortisol responses showed the following response pattern: Luteal 5 Men . Follicular 5 OC. The salivary cortisol responses to ACTH 1‐24 showed a similar response pattern: Luteal . Men . Follicular . OC. In contrast, total blood cortisol levels did not reveal any group difference between sexes or follicular versus luteal phase in either test. Although a similar salivary-free cortisol increase after awakening was found in the four groups, the circadian cortisol profile was significantly different throughout the first 4 hours of sampling. Questionnairederived psychological variables, as measured in the present study, could not explain the observed results. Conclusions: We conclude that gender, menstrual cycle phase, and OC use exert important effects on HPA responsiveness to psychosocial stress in healthy subjects. Although men seem to have a stronger hypothalamic drive in response to stressful stimulation than women, differences in salivary-free cortisol levels, at least in part, may be explained by estradiol-induced changes in corticosteroid-binding protein levels. ACTH and cortisol secretion is not affected by OC use per se but the amount of bioavailable unbound cortisol (“free”) is greatly reduced in this group of women after stimulation. Inasmuch as none of these differences between the study groups emerged in total blood cortisol levels, we strongly advocate for the simultaneous measurement of free and total cortisol levels in future studies on HPA functioning. Key words: psychosocial stress, HPA axis, sex differences, menstrual cycle, oral contraceptives, salivary cortisol, TSST, CBG.

Impact of gender, menstrual cycle phase, and oral contraceptives on the activity of the hypothalamus-pituitary-adrenal axis.

Cytochrome P450 enzymes that metabolize estrogens are expressed in the mammary gland, uterus, brain and other target tissues for estrogen action, and this results in the formation of hydroxylated estrogens in these tissues. Estradiol metabolites formed in target tissues at or near estrogen receptors may either be inactive or have important biological effects, and changes in the activities of estrogen-metabolizing enzymes in target tissues may profoundly influence estrogen action. Although some active estrogen metabolites exert hormonal effects in target tissues by interaction with the classical estrogen receptor, other metabolites appear to elicit unique biological responses that are not associated with activation of this receptor. Therefore, some of the many actions of estradiol may not be caused by estradiol per se, but may result from the formation of active estrogen metabolite(s) which function as local mediators or may activate their own unique receptors or effectors. This is an important area in need of more research. The present paper represents a review of the literature and perspectives by the authors on the functional role of estrogen metabolism in target tissues.

https://www.hormonebalance.org/images/documents/Zhu%2098estrogen%20metabolism%20in%20target%20cells%20Carc.pdf

Functional role of estrogen metabolism in target cells: review and perspectives.

OBJECTIVE Ghrelin is a new gastric hormone that has been identified as an endogenous ligand for the growth hormone (GH) secretagogue receptor subtype 1a (GHS-R1a). Ghrelin administration however not only stimulates GH secretion but also induces adiposity in rodents by increasing food intake and decreasing fat utilization. We hypothesized that impaired ghrelin secretion in anorexia nervosa may be involved in the pathogenesis of this eating disorder. To examine this hypothesis and to further investigate the role for ghrelin in regulating energy homeostasis, we analyzed circulating ghrelin levels in patients with anorexia nervosa and examined possible correlations with clinical parameters before and after weight gain. METHODS Plasma ghrelin levels were measured in overnight fasting plasma samples from 36 female patients with anorexia nervosa (age: 25.0+/-1.2 years, BMI: 15.2+/-0.2 kg/m(2)) before and after weight gain following psychotherapeutic treatment intervention in a psychosomatic institution. Plasma ghrelin levels were also measured in fasting plasma samples from 24 age-matched female controls (31+/-1.4 years, BMI: 22.9+/-0.45 kg/m(2)). For quantification of ghrelin levels a commercially available radioimmunoassay (Phoenix Pharmaceuticals, USA) was used. RESULTS Fasting plasma ghrelin levels in anorectic patients were significantly higher (1057+/-95 pg/ml) than in normal age-matched female controls (514+/-63 pg/ml n=24, P=0.02). Therapeutic intervention in a psychosomatic institution caused an BMI increase of 14% (P<0.001) leading to a significant decrease in circulating ghrelin levels of 25%, (P=0.001). A significant negative correlation between Deltaghrelin and DeltaBMI was observed (correlation coefficient: -0.47, P=0.005, n=36). CONCLUSION We show for the first time that fasting plasma levels of the novel appetite-modulating hormone ghrelin are elevated in anorexia nervosa and return to normal levels after partial weight recovery. These observations suggest the possible existence of ghrelin resistance in cachectic states such as caused by eating disorders. Future studies are necessary to investigate putative mechanisms of ghrelin resistance such as a possible impairment of intracellular ghrelin receptor signaling in pathophysiological states presenting with cachexia.

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Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa

A review of brain aromatase cytochrome P450

This review summarizes the current knowledge of the biosynthesis of neurosteroids in the human brain, the enzymes mediating these reactions, their localization and the putative effects of neurosteroids. Molecular biological and biochemical studies have now firmly established the presence of the steroidogenic enzymes cytochrome P450 cholesterol side-chain cleavage (P450SCC), aromatase, 5alpha-reductase, 3alpha-hydroxysteroid dehydrogenase and 17beta-hydroxysteroid dehydrogenase in human brain. The functions attributed to specific neurosteroids include modulation of gamma-aminobutyric acid A (GABAA), N-methyl-d-aspartate (NMDA), nicotinic, muscarinic, serotonin (5-HT3), kainate, glycine and sigma receptors, neuroprotection and induction of neurite outgrowth, dendritic spines and synaptogenesis. The first clinical investigations in humans produced evidence for an involvement of neuroactive steroids in conditions such as fatigue during pregnancy, premenstrual syndrome, post partum depression, catamenial epilepsy, depressive disorders and dementia disorders. Better knowledge of the biochemical pathways of neurosteroidogenesis and their actions on the brain seems to open new perspectives in the understanding of the physiology of the human brain as well as in the pharmacological treatment of its disturbances.

/pdf/neurosteroid-metabolism-in-the-human-brain-51u15vyy9u.pdf

Neurosteroid metabolism in the human brain.

The in vitro aromatization and 5alpha-reduction of androgens to estrogens and dihydrotestosterone (DHT) were determined in incubations of microdissected brain regions of male and female gonadectomized, adrenalectomized rats. Metabolites formed from [1alpha,2alpha-3H]androstenedione or [1alpha,2alpha-3H]testosterone were purified by celite liquid-liquid partition chromatography, silica gel chromatography and recrystallization to stable 3H/14C ratios. The medial preoptic nucleus-anterior hypothalamic nucleus exhibited the highest aromatase activity and the second highest conversion to DHT. The lateral preoptic and lateral hypothalamic nuclei showed little aromatase activity yet exhibited high rates of formation of DHT. The medial basal hypothalamus showed the second highest level of aromatase activity but consistently formed the lowest amount of DHT. The discrect anatomical localization of these enzymatic conversions is suggestive of their being involved in the physiological actions of androgens.

Aromatization and 5α-Reduction of Androgens in Discrete Hypothalamic and Limbic Regions of the Male and Female Rat1

The norepinephrine (NE) and dopamine (DA) concentrations of the medial preoptic nucleus (MPN), suprachiasmatic nucleus (SCN), arcuate nucleus (AN), ventromedial nucleus (VMN) and median eminence (ME) were measured during the estrous cycle. Nuclei were microdissected and assayed using the catecho1-0-methyl transferase enzymatic method. A significant increase in NE was observed between the morning and afternoon of proestrus (P) in the SCN. In contrast, no significant changes in DA were detected in any area on P. No change in NE or DA was found between the morning and afternoon of diestrus 1 (Dl). These findings are consistent with NE-containing neurons being involved in the surge of LH on the afternoon of proestrus.

Concentrations of dopamine and norepinephrine in discrete hypothalamic nuclei during the rat estrous cycle1

OBSTETRICAL AND GYNECOLOGICAL SURVEY AROMATIZATION AND 5α REDUCTION OF ANDROGENS IN DISCRETE HYPOTHALAMIC AND LIMBIC REGIONS OF THE MALE AND FEMALE RAT

Michael K. Selmanoff

Papers

Aromatization and 5α-Reduction of Androgens in Discrete Hypothalamic and Limbic Regions of the Male and Female Rat1

Concentrations of dopamine and norepinephrine in discrete hypothalamic nuclei during the rat estrous cycle1

OBSTETRICAL AND GYNECOLOGICAL SURVEY AROMATIZATION AND 5α REDUCTION OF ANDROGENS IN DISCRETE HYPOTHALAMIC AND LIMBIC REGIONS OF THE MALE AND FEMALE RAT