Gonadotropin Inhibitory Hormone and Its Receptor: Potential Key to the Integration and Coordination of Metabolic Status and Reproduction

Since its discovery as a novel gonadotropin inhibitory peptide in 2000, the central and peripheral roles played by gonadotropin-inhibiting hormone (GnIH) have been significantly expanded. This is highlighted by the wide distribution of its receptor (GnIH-R) within the brain and throughout multiple peripheral organs and tissues. Furthermore, as GnIH is part of the wider RF-amide peptides family, many orthologues have been characterized across vertebrate species, and due to the promiscuity between ligands and receptors within this family, confusion over the nomenclature and function has arisen. In this review, we intend to first clarify the nomenclature, prevalence, and distribution of the GnIH-Rs, and by reviewing specific localization and ligand availability, we propose an integrative role for GnIH in the coordination of reproductive and metabolic processes. Specifically, we propose that GnIH participates in the central regulation of feed intake while modulating the impact of thyroid hormones and the stress axis to allow active reproduction to proceed depending on the availability of resources. Furthermore, beyond the central nervous system, we also propose a peripheral role for GnIH in the control of glucose and lipid metabolism at the level of the liver, pancreas, and adipose tissue. Taken together, evidence from the literature strongly suggests that, in fact, the inhibitory effect of GnIH on the reproductive axis is based on the integration of environmental cues and internal metabolic status.

Ischemic Stroke, Glucocorticoids, and Remote Hippocampal Damage: A Translational Outlook and Implications for Modeling

Progress in treating ischemic stroke (IS) and its delayed consequences has been frustratingly slow due to the insufficient knowledge on the mechanism. One important factor, the hypothalamic-pituitary-adrenocortical (HPA) axis is mostly neglected despite the fact that both clinical data and the results from rodent models of IS show that glucocorticoids, the hormones of this stress axis, are involved in IS-induced brain dysfunction. Though increased cortisol in IS is regarded as a biomarker of higher mortality and worse recovery prognosis, the detailed mechanisms of HPA axis dysfunction involvement in delayed post-stroke cognitive and emotional disorders remain obscure. In this review, we analyze IS-induced HPA axis alterations and supposed association of corticoid-dependent distant hippocampal damage to post-stroke brain disorders. A translationally important growing point in bridging the gap between IS pathogenesis and clinic is to investigate the involvement of the HPA axis disturbances and related hippocampal dysfunction at different stages of SI. Valid models that reproduce the state of the HPA axis in clinical cases of IS are needed, and this should be considered when planning pre-clinical research. In clinical studies of IS, it is useful to reinforce diagnostic and prognostic potential of cortisol and other HPA axis hormones. Finally, it is important to reveal IS patients with permanently disturbed HPA axis. Patients-at-risk with high cortisol prone to delayed remote hippocampal damage should be monitored since hippocampal dysfunction may be the basis for development of post-stroke cognitive and emotional disturbances, as well as epilepsy.

Stress Axis in the Cancer Patient: Clinical Aspects and Management

Hypothalamus–pituitary–adrenal (HPA) axis alterations are common in cancer patients, mainly due to the different antitumoral therapies, which lead to several acute and late endocrine side effects. This review summarizes the most recent evidence regarding HPA derangement, both in patients with active neoplasms and in cancer survivors, with particular attention to the impact of the different antitumoral treatments, focusing on the major clinical aspects. While acute hormone failure usually results from injury caused directly by tumor burden or surgical interventions, short- and long-term effects are generally due to chemotherapy, radiotherapy and, as more recently shown, to different types of targeted- and immuno-therapy. Adrenal insufficiency (AI) is mostly caused by pituitary or hypothalamic injury rather than a direct damage of the adrenal gland. Moreover, other treatments commonly employed as supportive therapy or in the context of palliative care (i.e., glucocorticoids, opioids) can lead to HPA dysfunction. Epidemiology and pathophysiology of stress axis alterations in cancer patients still require clarification. Since AI may represent a life-threatening condition, monitoring adrenal function in cancer patients is mandatory, especially in subjects who experience fatigue or during stress conditions, in order to promptly start replacement treatment when needed.

Prediction of eruption of the lower third molars depending on their position relative to the “stress axis”

The article discusses the important problem of the presence and location of the primordia of third molars and the possibility of their eruption without affecting the dentition. The problem is relevant and is being studied by domestic and foreign specialists from different angles with the use of various diagnostic techniques. This article is based on the analysis of the most accessible and most frequently used X-ray diagnostic method – the panoramic X-ray.The aim was to study the prediction of eruption of the lower third molars depending on their position relative to the “stress axis”.84 panoramic images of the patients aged 12‒25 years were analyzed. To study the OPTG, the method of Fishchev et al. (2012), which determines the position of the lower third molars relative to the “stress axis”, and Demirjian’s modified method (1973), which determines the stage of their formation, were used. The data were processed statistically.The results are presented in tables and diagrams, as well as in correlations. Their interpretation is discussed. These data allowed us to draw conclusions about a significant change only in the angle of inclination and the stages of formation of the roots of the third molars of the lower jaw, about the absence of changes in the gonial angle and the position of the studied teeth with age. At the same time, it was found that the location of the coronal part of the third molars below the “stress axis” does not worsen the prediction of their eruption.

Morpholino-mediated knockdown of the brain mineralocorticoid receptor affects glucocorticoid signaling and neuroplasticity in wild ocellated wrasse (Symphodus ocellatus)

Uncovering the genetic, physiological, and developmental mechanisms underlying phenotypic variation is necessary for understanding how genetic and genomic variation shape phenotypic variation and for discovering possible targets of selection. Although the neural and endocrine mechanisms underlying social behavior are evolutionarily ancient, we lack an understanding of the proximate causes and evolutionary consequences of variation in these mechanisms. Here, we examine in the natural environment the behavioral, neuromolecular, and fitness consequences of a morpholino-mediated knockdown of the mineralocorticoid receptor (MR) in the brain of nesting males of the ocellated wrasse, Symphodus ocellatus, a species with male alternative reproductive tactics. Even though MR knockdown did not significantly change male behavior directly, this experimental manipulation strongly altered glucocorticoid signaling and neuroplasticity in the preoptic area, the putative hippocampus homolog, and the putative basolateral amygdala homolog. We also found that individual variation in stress axis gene expression and neuroplasticity is strongly associated with variation in male behavior and fitness-related traits. The brain region-specific effects of MR knockdown on phenotypic integration in the wild reported here suggest specific neuroendocrine and neuroplasticity pathways that may be targets of selection.

The Role of GDF15 as a Myomitokine

Growth differentiation factor 15 (GDF15) is a cytokine best known for affecting systemic energy metabolism through its anorectic action. GDF15 expression and secretion from various organs and tissues is induced in different physiological and pathophysiological states, often linked to mitochondrial stress, leading to highly variable circulating GDF15 levels. In skeletal muscle and the heart, the basal expression of GDF15 is very low compared to other organs, but GDF15 expression and secretion can be induced in various stress conditions, such as intense exercise and acute myocardial infarction, respectively. GDF15 is thus considered as a myokine and cardiokine. GFRAL, the exclusive receptor for GDF15, is expressed in hindbrain neurons and activation of the GDF15–GFRAL pathway is linked to an increased sympathetic outflow and possibly an activation of the hypothalamic-pituitary-adrenal (HPA) stress axis. There is also evidence for peripheral, direct effects of GDF15 on adipose tissue lipolysis and possible autocrine cardiac effects. Metabolic and behavioral outcomes of GDF15 signaling can be beneficial or detrimental, likely depending on the magnitude and duration of the GDF15 signal. This is especially apparent for GDF15 production in muscle, which can be induced both by exercise and by muscle disease states such as sarcopenia and mitochondrial myopathy.

Modulation by Ozone of Glucocorticoid-Regulating Factors in the Lungs in Relation to Stress Axis Reactivity

Exposure to air pollutants increases levels of circulating glucocorticoid stress hormones that exert profound effects relevant to health and disease. However, the nature and magnitude of tissue-level effects are modulated by factors that regulate local glucocorticoid activity; accordingly, inter-individual differences could contribute to susceptibility. In the present study, we characterized effects of ozone (O3) inhalation on glucocorticoid-regulating factors in the lungs of rat strains with contrasting hypothalamic–pituitary–adrenal stress axis responses. Hyper-responsive Fischer (F344) and less responsive Lewis (LEW) rats were exposed to air or 0.8 ppm O3 for 4 h by nose-only inhalation. Levels of the high-specificity and -affinity corticosteroid-binding globulin protein increased in the lungs of both strains proportional to the rise in corticosterone levels following O3 exposure. Ozone reduced the ratio of 11β-hydroxysteroid dehydrogenase type 1 (HSDB1)/HSDB2 mRNA in the lungs of F344 but not LEW, indicating strain-specific transcriptional regulation of the major glucocorticoid metabolism factors that control tissue-level action. Intercellular adhesion molecule (ICAM)-1 and total elastase activity were increased by O3 in both strains, consistent with extravasation and tissue remodeling processes following injury. However, mRNA levels of inflammatory markers were significantly higher in the lungs of O3-exposed LEW compared to F344. The data show that strain differences in the glucocorticoid response to O3 are accompanied by corresponding changes in regulatory factors, and that these effects are collectively associated with a differential inflammatory response to O3. Innate differences in glucocorticoid regulatory factors may modulate the pulmonary effects of inhaled pollutants, thereby contributing to differential susceptibility.