Altered diurnal pattern of steroid hormones in relation to various behaviors, external factors and pathologies: A review.

The adrenal and gonadal stress steroids [i.e., cortisol, testosterone and dehydroepiandrosterone (DHEA)] have gathered considerable attention in the last few decades due to their very broad physiological and psychological actions. Their diurnal patterns have become a particular focus following new data implicating altered diurnal hormone patterns in various endocrine, behavioral and cardiovascular risk profiles. In this review of the current literature, we present a brief overview of the altered diurnal patterns of these hormones that may occur in relation to chronic stress, nutritional behaviors, physical exercise, drugs and sleep deprivation/shift. We also present data on the altered diurnal hormone patterns implicated in cardiometabolic and psychiatric/neurologic diseases, cancer and other complex pathologies. We consider the occasionally discrepant results of the studies, and summarize the current knowledge in this new field of interest, underlining the potential effects on both biological and psychological functioning, and assess the implications of these effects. Last, we conclude with some practical considerations and perspectives.

The association between self-reported daily hassles and cortisol levels in depression and anxiety in community living older adults.

OBJECTIVES: The aim of this study was to assess whether the association, in a naturalistic setting, between daily hassles and diurnal salivary cortisol differs in the presence of depression and anxiety in older adults. METHODS: Data were assessed in a large representative community sample of older adults (n = 1760). A multinomial analysis was used to study as an outcome variable: no disorder, depression only, anxiety only and depression and anxiety, as a function of daily hassles and cortisol levels controlling for age, gender and time of saliva collection. Multivariate regression analyses were also carried out to test the association between daily hassles and cortisol levels stratified by depression and anxiety status. RESULTS: A significant positive association was observed between the number of daily hassles reported and cortisol levels in participants with no depression and no anxiety and in participants with anxiety. Participants without depression and anxiety, and those with depression only, had significant lower cortisol levels later in the day. This was not observed in respondents with anxiety. CONCLUSION: Stressors such as daily hassles are associated with cortisol secretion in depression and anxiety in older adults in a large epidemiologic setting.

Cognitive decline in patients with Cushing's syndrome.

Chronic exposure to elevated glucocorticoid levels in Cushing's syndrome (CS), is associated with deficits in cognitive function and in emotion. The hippocampus plays a crucial role in the behavioral manifestations of the syndrome as it is richest in glucocorticoid receptors and is thus particularly vulnerable to glucocorticoid excess. The wide distribution of glucocorticoid receptors throughout the cerebral cortex, however, suggests that several cognitive functions can also be affected by the dysregulation of glucocorticoids. In this study, we investigated how an excess of glucocorticoid hormones affects cognitive processes. Nineteen patients with chronic hypercortisolemia due to CS were compared to healthy controls matched for age, sex, education, and occupation in tests of processing of visual and spatial information, memory, reasoning and concept formation, language and verbal functions, and attention. Multivariate and univariate analyses revealed overall differences in tests of treatment of visual and spatial information, reasoning and concept formation as well as in verbal and language performance, with poorer performance from CS patients. Differences were also observed in nonverbal aspects of memory and in attention tasks. The results suggest that chronic exposure to elevated levels of cortisol is associated with deficits in several areas of cognition, particularly those involving processing of selective attention and visual components. This study also shows that hormones play an important role in the modulation of cognitive function and that their influence on cerebral structure and function merits closer scrutiny.

Auditory cerebral lateralization following cross-gender hormone therapy.

In this study, 10 men, 10 women, and 13 genetic male transsexuals, all of them righthanded, were tested on two verbal (CV and nonsense polysyllables) and two nonverbal (melodies and triple tone [3T]) dichotic tasks to investigate relations between hormone therapy and auditory cerebral specialization for speech and non speech stimuli in adults. At time of testing, all transsexuals had been made under hormonal treatment for at least one year and eight had had corrective surgery. ANOVA results showed a right ear advantage and similar pattern of performance for the three groups in the treatment of speech. In nonverbal tasks, interactions revealed a left ear advantage in the processing of melodies and 3T for men only: women and transsexuals exhibited similar performance in both nonverbal tasks. In accord with generalization from the animal literature, cautious interpretation of the data is some possible hormonal involvement, in adults, in the modulation of right hemispheric cognitive processing.

Life after birth: the influence of steroid hormones on cerebral structure and function is not fixed prenatally.

Bryden, McManus, and Bulman-Fleming conclude that available empirical evidence does not support the Geschwind-Behan-Galaburda model of cerebral lateralization. One of the central assumptions of the model is that fetal testosterone plays a determinant role in the development of anomalous specialization and is associated with various behavioral, cognitive, and immunological disorders. The influence of testosterone, however, is not limited to the perinatal period. We show that hormonal effects constitute lifelong influences on aspects of brain architecture and function. These influences represent a little-known and discussed--but extremely relevant--dimension of our understanding of the biological bases of behavior.

MMQ cells: a model for evaluating the role of G proteins in the modulation of prolactin release.

It is well known that dopamine (DA) inhibits while vasoactive intestinal peptide (VIP) and angiotensin II (ANG II) stimulate prolactin (PRL) release from normal anterior pituitary lactotrophs; however, elucidation of the intracellular mechanisms involved in these effects has been hindered by the cellular heterogeneity of the anterior pituitary. MMQ cells, isolated from the PRL-secreting rat pituitary tumor 7315a is an interesting model since they only secrete PRL. In order to determine whether and which GTP-binding (G) proteins are involved in the modulation of cyclic 3',5'-adenosine monophosphate (cAMP) accumulation and phospholipids turnover and eventually PRL release, we have performed studies with MMQ cells. For this purpose, the levels of various G proteins (alpha o, alpha s, alpha i, alpha q and beta) and their mRNAs, measured by Western and Northern blots respectively, were correlated with intracellular cAMP accumulation in response to DA, VIP or DA plus VIP, and with inositol phosphates (IPx) formation in response to ANG II, DA or DA plus ANG II. This study shows that, when compared to normal pituitary tissue, the levels of alpha o, alpha o2 and alpha i3 were significantly decreased in MMQ cells; those of alpha o1, alpha i (alpha i1 + alpha i2), alpha s42 and alpha q were very low or undetectable while those of alpha s47 and beta were normal. DA was unable to inhibit basal PRL release and cAMP accumulation. VIP increased both cAMP accumulation and PRL release, while cAMP accumulation elicited by VIP could be suppressed by DA. BAY K 8644-induced PRL release also could be suppressed by DA.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of prolactin release by gonadotropin-releasing hormone-associated Peptide in benign, dopamine-sensitive and in malignant, dopamine-resistant pituitary tumors.

Since the gonadotropin-releasing hormone-associated peptide (GAP) has been reported to be capable of inhibiting prolactin release from normal lactotrophs, with the present study we have examined the in vitro effects of GAP on prolactin release in an estrone-induced, dopamine-sensitive rat pituitary adenoma and two malignant, transplantable and dopamine-resistant rat pituitary tumors, 7315a and MtTW15. Enzymatically dispersed cells obtained from the three types of tumor were cultured in multiwell dishes for 4 days. On the fifth day, the cells were exposed for 4 h to human GAP 1-56 or to the analog GAP 42-56 or to rat GAP 1-53, at various concentrations. In some experiments, the effect of a pretreatment of the cells for 16 h with pertussis toxin before exposure to human GAP was also evaluated. In the three tissues, rat GAP was able to inhibit prolactin release in a dose-dependent manner. Human GAP 1-56 and GAP 42-56 were able to inhibit prolactin release in a dose-dependent manner in all cells except those of the MtTW15 tumor. Furthermore, in adenomatous cells, the inhibitory effects of these peptides were suppressed by pretreatment of the cells with pertussis toxin. These findings indicate that GAP is capable of inhibiting prolactin release even in dopamine-resistant pituitary tumors. This inhibition is exerted through a pertussis toxin-sensitive G-protein-dependent signaling mechanism in adenomatous cells.

G proteins in normal rat pituitaries and in prolactin-secreting rat pituitary tumors.

It is still undetermined which GTP-binding (G) protein is involved in the regulation of prolactin (PRL) release and through which effector. This study shows that, when compared to normal pituitary tissue, the levels of alpha o protein were very low in dopamine (DA)-resistant, PRL-secreting pituitary tumors 7315a and MtTW15, while alpha o mRNA was present in the two tumors. In the MtTW15 tumor alpha i1, alpha i2 and alpha i3 levels were decreased while those of alpha s42 and alpha s47 were increased, and in the 7315a tumor alpha i2, alpha i3 and beta levels were decreased and those of alpha s47 increased. In an estrone-induced, DA-sensitive prolactinoma the levels of alpha i3 were greatly reduced. DA was unable to inhibit basal PRL release by 7315a and MtTW15 and basal cAMP accumulation by adenomatous and MtTW15 cells. Vasoactive intestinal peptide (VIP) increased both cAMP accumulation and PRL release by all cell preparations which could be suppressed by DA with adenomatous and 7315a but not with MtTW15 cells. These and previously published results provide circumstantial evidence that alpha o, alpha i1 and alpha i3 are all involved in the transduction of the DA inhibitory message while alpha s47 transduces cAMP activating messages and alpha s42 is responsible for the constitutive activation of L-type Ca2+ channels, adenylate cyclase and baseline PRL release.

Control of phospholipid turnover and prolactin release in a dopamine-sensitive, prolactin-secreting rat pituitary adenoma and in two dopamine-resistant, prolactin-secreting rat pituitary tumors.

Abstract The secretion of prolactin by the pituitary gland is under a tonic inhibitory control exerted by tubero-infundibular dopamine. Recently, it has been suggested that dopamine may exert its action by inhibiting production of inositol phosphates and mobilization of intracellular Ca(2+). To study the effects of dopamine on the production of inositol phosphates and prolactin release, we have utilized an estrone-induced, dopamine-sensitive rat pituitary adenoma and two transplantable and dopamine-resistant rat pituitary tumors, 7315a and MtTW15. Purified cells, obtained from the three tissues, were incubated for 30 min in media with drugs (thyrotropin-releasing hormone or angiotensin II) stimulating inositol phosphates and prolactin release, in the presence or the absence of dopamine. Basal production of inositol phosphates and prolactin release by adenomatous lactotrophs were inhibited by dopamine. Thyrotropin-releasing hormone and angiotensin II stimulated inositol phosphates by adenomatous and 7315a cells. This effect was antagonized by dopamine in adenomatous cells. Prolactin release by adenomatous cells only was stimulated by thyrotropin-releasing hormone and angiotensin II. This stimulation was inhibited by dopamine. The results show differences, in the mechanisms of regulation of prolactin release, between adenoma and transplantable pituitary tumors as well as between the two tumors themselves. These differences may be responsible, in part, for the resistance of the two transplantable pituitary tumors to the inhibitory effects of dopamine on prolactin release and tumor size. Our results obtained both with adenoma and tumoral cells also suggest that inositol phosphates probably intervene only in the late phases of dopamine inhibition of prolactin release and only in the presence of a normal Ca(2+) signaling system.

Regulation of Basal and stimulated prolactin release in prolactin-secreting rat pituitary tumors*.

Abstract To better understand the mechanisms of the inhibitory effects of dopamine on pituitary prolactin release, we have utilized an estrone-induced, benign and dopamine-sensitive rat pituitary adenoma and two malignant, transplantable and dopamine-resistant rat pituitary tumors, 7315a and MITW15. Enzymatically dispersed and Percoll purified cells obtained from the three tissues were incubated for 30 min in media with or without Na(+) and in the presence or the absence of dopamine and/or various prolactin releasers for evaluating the secretion of prolactin under baseline and experimental conditions. In some experiments, the cells were pretreated for 16 h with pertussis toxin to evaluate the eventual presence and role of pertussis toxin-sensitive G proteins. Dopamine inhibited baseline prolactin release by adenomatous lactotrophs in a Na(+)-dependent manner, but was totally inactive with 7315a and MtTW15 cells. The Ca(2+) channel agonist BAY K 8644 stimulated prolactin release with all three preparations and its effects were enhanced by a Na(+)-free medium. Dopamine antagonized the stimulatory effects of BAY K 8644 with adenomatous and 7315a cells only, even in the absence of Na(+). Pertussis toxin pretreatment significantly increased baseline prolactin release by adenomatous and MtTW15 cells and abolished dopamine inhibition of adenomatous lactotrophs baseline hormone release. BAY K 8644, TRH and vasoactive intestinal peptide, stimulated prolactin release by adenomatous cells and this effect was antagonized by dopamine in a pertussis toxin-sensitive manner. All prolactin releasers, except TRH, were effective also with 7315a cells, and its actions were not blocked by pertussin toxin. The stimulatory effects of BAY K 8644 and vasoactive intestinal peptide on 7315a cells were enhanced by pertussis toxin pretreatment. The results obtained with an almost pure preparation of adenomatous lactotrophs confirm the existence of a dual mechanism of dopamine inhibitory action on prolactin release: 1) a Na(+)-dependent action exerted on baseline, and 2) a Na(+)-independent action exerted on stimulated prolactin release. They also indicate that both actions are exerted through pertussis toxin-sensitive G proteins. Furthermore, our results show the presence in transplantable pituitary tumors 7315a and MtTW15 of multiple and diverse anomalies in the regulation of prolactin release probably due, at least partly, to anomalies of one or more G proteins and/or neurotransmitter receptors.