Testosterone administration in human social neuroendocrinology: Past, present, and future.

Over the past 20 years, social neuroendocrinology researchers have developed pharmacological challenge paradigms to assess the extent to which testosterone plays a causal role in human psychological and behavioural processes. The current paper provides a brief summary of this research and offers recommendations for future research examining the neuroendocrine mechanisms underlying human behaviour.

An updated field guide for snark hunting: Comparative contributions to behavioral neuroendocrinology in the era of model organisms.

Studying neuroendocrine behavioral regulatory mechanisms in a variety of species across vertebrate groups is critical for determining how they work in natural contexts, how they evolved, and ultimately what can be generalized from them, potentially even to humans. All of the above are difficult, at best, if work within our field is exclusively done in traditional laboratory organisms. The importance of comparative approaches for understanding the relationships between hormones and behavior has been recognized and advocated for since our field's inception through a series of papers centered upon a poetic metaphor of Snarks and Boojums, all of which have articulated the benefits that come from studying a diverse range of species and the risks associated with a narrow focus on "model organisms." This mini-review follows in the footsteps of those powerful arguments, highlighting some of the comparative work since the latest interactions of the metaphor that has shaped how we think about three major conceptual frameworks within our field, two of them formalized - the Organization/Activation Model of sexual differentiation and the Social Brain Network - and one, context-dependency, that is generally associated with virtually all modern understandings of how hormones affect behavior. Comparative approaches are broadly defined as those in which the study of mechanism is placed within natural and/or evolutionary contexts, whether they directly compare different species or not. Studies are discussed in relation to how they have either extended or challenged generalities associated with the frameworks, how they have shaped subsequent work in model organisms to further elucidate neuroendocrine behavioral regulatory mechanisms, and how they have stimulated work to determine if and when similar mechanisms influence behavior in our own species.

Estrogenic regulation of memory: The first 50 years.

This review highlights fifty years of progress in research on estradiol's role in regulating behavior(s). It was initially thought that estradiol was only involved in regulating estrus/menstrual cycles and concomitant sexual behavior, but it is now clear that estradiol also influences the higher order neural function of cognition. We provide a brief overview of estradiol's regulation of memory and some mechanisms which underlie its effects. Given systemically or directly into the hippocampus, to ovariectomized female rodents, estradiol or specific agonists, enhance learning and/or memory in a variety of rodent cognitive tasks. Acute (within minutes) or chronic (days) treatments enhance cognitive functions. Under the same treatment conditions, dendritic spine density on pyramidal neurons in the CA1 area of the hippocampus and medial prefrontal cortex increase which suggests that these changes are an important component of estrogen's ability to impact memory processes. Noradrenergic, dopaminergic and serotoninergic activity are also altered in these areas following estrogen treatments. Memory enhancements and increased spine density by estrogens are not limited to females but are also present in castrate males. In the next fifty years, neuroscientists need to determine how currently described neural changes mediate improved memory, how interactions among areas important for memory promote memory and the potential significance of neurally derived estrogens in normal cognitive processing. Answering these questions may provide significant advances for treatment of dementias as well as age and neuro-degenerative disease related memory loss.

Hormones and Behavior: An emergent journal.

Hormones and Behavior was founded in 1969 by Frank A. Beach and members of his laboratory. Prior to the founding there was no journal specifically devoted to hormones and behavior. This paper explores how the editorship of the journal has developed over the first 50 years, going from the initial three male editors to the current female editor-in-chief, five associate editors (four men and one women), and a 98 member editorial board consisting of 46 men and 52 women. Early concerns that a specialty journal of hormones and behavior might ghettoize the field did not come to pass and the visibility and impact of the journal has helped to expand the spread of the field, now called Behavioral Neuroendocrinology. This growth accelerated with the creation of the Society for Behavioral Neuroendocrinology in 1996 and the adoption of Hormones and Behavior as the Society's official journal. The growth has been striking with total annual citations going from 1321 per year in 1997 to the current 10,874 annual citations. The journal's impact factor (JIF), 1.42 in 1997, has increased to the current (2018) JIF of 3.95. Over the 50 years of Hormones and Behavior's existence it has emerged as a principle voice of the Hormones and Behavior community. It will be intriguing to see what the next 50 years reveals.

Sexual differentiation of brain and other tissues: Five questions for the next 50 years.

This paper is part of the celebration of the 50th anniversary of founding of the journal Hormones and Behavior, the official journal of the Society for Behavioral Neuroendocrinology. All sex differences in phenotypic development stem from the sexual imbalance in X and Y chromosomes, which are the only known differences in XX and XY zygotes. The sex chromosome genes act within cells to cause differences in phenotypes of XX and XY cells throughout the body. In the gonad, they determine the type of gonad, leading to differences in secretion of testicular vs. ovarian hormones, which cause further sex differences in tissue function. These current ideas of sexual differentiation are briefly contrasted with a hormones-only view of sexual differentiation of the last century. The multiple, independent action of diverse sex-biasing agents means that sex-biased factors can be synergistic, increasing sex differences, or compensatory, making the two sexes more equal. Several animal models have been fruitful in demonstrating sex chromosome effects, and interactions with gonadal hormones. MRI studies of human brains demonstrate variation in brain structure associated with both differences in gonadal hormones, and in the number of X and Y chromosomes. Five unanswered questions are posed as a challenge to future investigators to improve understanding of sexual differentiation throughout the body.

Mini-review: Epigenetic mechanisms that promote transgenerational actions of endocrine disrupting chemicals: Applications to behavioral neuroendocrinology.

It is our hope this mini-review will stimulate discussion and new research. Here we briefly examine the literature on transgenerational actions of endocrine disrupting chemicals (EDCs) on brain and behavior and their underlying epigenetic mechanisms including: DNA methylation, histone modifications, and non-coding RNAs. We stress that epigenetic modifications need to be examined in a synergistic manner, as they act together in situ on chromatin to change transcription. Next we highlight recent work from one of our laboratories (VGC). The data provide new evidence that the sperm genome is poised for transcription. In developing sperm, gene enhancers and promoters are accessible for transcription and these activating motifs are also found in preimplantation embryos. Thus, DNA modifications associated with transcription factors during fertilization, in primordial germ cells (PGCs), and/or during germ cell maturation may be passed to offspring. We discuss the implications of this model to EDC exposures and speculate on whether natural variation in hormone levels during fertilization and PGC migration may impart transgenerational effects on brain and behavior. Lastly we discuss how this mechanism could apply to neural sexual differentiation.

How technical progress reshaped behavioral neuroendocrinology during the last 50 years and some methodological remarks.

The first issue of Hormones and Behavior was published 50 years ago in 1969, a time when most of the techniques we currently use in Behavioral Endocrinology were not available. Researchers have during the last 5 decades developed techniques that allow measuring hormones in small volumes of biological samples, identify the sites where steroids act in the brain to activate sexual behavior, characterize and quantify gene expression correlated with behavior expression, modify this expression in a specific manner, and manipulate the activity of selected neuronal populations by chemogenetic and optogenetic techniques. This technical progress has considerably transformed the field and has been very beneficial for our understanding of the endocrine controls of behavior in general, but it did also come with some caveats. The facilitation of scientific investigations came with some relaxation of methodological exigency. Some critical controls are no longer performed on a regular basis and complex techniques supplied as ready to use kits are implemented without precise knowledge of their limitations. We present here a selective review of the most important of these new techniques, their potential problems and how they changed our view of the hormonal control of behavior. Fortunately, the scientific endeavor is a self-correcting process. The problems have been identified and corrections have been proposed. The next decades will obviously be filled with exciting discoveries in behavioral neuroendocrinology.

The behavioral neuroendocrinology of maternal behavior: Past accomplishments and future directions.

Research on the neuroendocrine-endocrine-neural regulation of maternal behavior has made significant progress the past 50 years. In this mini-review progress during this period has been divided into five stages. These stages consist of advances in the identification of endocrine factors that mediate maternal care, the characterization of the neural basis of maternal behavior with reference to endocrine actions, the impact of developmental and experiential states on maternal care, the dynamic neuroplastic maternal brain, and genes and motherhood. A final section concludes with a discussion of future directions in the field of the neurobiology/neuroendocrinology of motherhood.

Dads: Progress in understanding the neuroendocrine basis of human fathering behavior.

We outline the progress on the hormonal basis of human paternal behavior during the past twenty years. Advances in understanding the roles of testosterone, prolactin, oxytocin and vasopressin in fathering behavior are described, along with recent research on hormonal interactions, such as those between testosterone and cortisol, and testosterone and the peptide hormones. In addition, we briefly describe the recent leaps forward in elucidating the neurobiological and neuroendocrine basis of fatherhood, made possible by fMRI technology. Emerging from this literature is a developing and complicated story about fatherhood, highlighting the need to further understand the interplay between behavior, physiology, social context, and individual genetic variation. Given the changing roles of parents in many societies, the continued growth of this research area will provide a strong empirical knowledge base about paternal behavior on which to create policies promoting fathers' involvement in their infants' lives.

Human social neuroendocrinology: Review of the rapid effects of testosterone.

Contribution to Special Issue on Fast effects of steroids. It is well documented that testosterone concentrations change rapidly within reproductively relevant contexts (e.g., competition, mate-seeking). It has been argued that such rapid changes in testosterone may serve to adaptively fine-tune ongoing and/or future social behaviour according to one's social environment. In this paper, we review human correlational and experimental evidence suggesting that testosterone fluctuates rapidly in response to competition and mate-seeking cues, and that such acute changes may serve to modulate ongoing and/or future social behaviours (e.g., risk-taking, competitiveness, mate-seeking, and aggression). Some methodological details, which limit interpretation of some of this human work, are also discussed. We conclude with a new integrative model of testosterone secretion and behaviour, the Fitness Model of Testosterone Dynamics. Although we focus primarily on human aggression in this review, we also highlight research on risk-taking, competitiveness, and mate-seeking behaviour.

EDTORIAL_.

Why did we prepare this supplement and why it is about interdisciplinary public health issues? It is rather difficult question, but with a simple answer. Neurology field, neuroendocrinology field and many other areas of medicine are actually very important partners for public health professionals. Public health promotes and protects the health of people and the communities where they live, learn, work and play. While doctors treat people who are sick, those of us working in public health try to prevent people from getting sick or injured in the first place.

Current status and future perspectives: TSPO in steroid neuroendocrinology.

The mitochondrial translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor (PBR), has received significant attention both as a diagnostic biomarker and as a therapeutic target for different neuronal disease pathologies. Recently, its functional basis believed to be mediating mitochondrial cholesterol import for steroid hormone production has been refuted by studies examining both in vivo and in vitro genetic Tspo-deficient models. As a result, there now exists a fundamental gap in the understanding of TSPO function in the nervous system, and its putative pharmacology in neurosteroid production. In this review, we discuss several recent findings in steroidogenic cells that are in direct contradiction to previous studies, and necessitate a re-examination of the purported role for TSPO in de novo neurosteroid biosynthesis. We critically examine the pharmacological effects of different TSPO-binding drugs with particular focus on studies that measure neurosteroid levels. We highlight the basis of key misconceptions regarding TSPO that continue to pervade the literature, and the need for interpretation with caution to avoid negative impacts. We also summarize the emerging perspectives that point to new directions that need to be investigated for understanding the molecular function of TSPO, only after which the true potential of this therapeutic target in medicine may be realized.

Seguridad y efectividad del tratamiento con hormona de crecimiento: estudio GeNeSIS en España / Safety and efficacy of growth hormone treatment: GeNeSIS study in Spain

INTRODUCCIÓN: La información específica de cada país sobre el tratamiento pediátrico con hormona de crecimiento (GH) proviene de estudios multinacionales. MÉTODOS: En España, 1.294 niños participaron en el estudio internacional y observacional sobre genética y neuroendocrinología de la talla baja (GeNeSIS). En los pacientes tratados con GH (n=1.267) se evaluaron los acontecimientos adversos. En aquellos con deficiencia de GH (DGH, 78%) también se evaluó la efectividad. RESULTADOS: La media de edad al inicio del estudio fue 9,8 años. La mediana (Q1-Q3) de duración del tratamiento fue 2,8 (1,6-4,4) años y la dosis inicial de GH 0,22 (0,20-0,25) mg/kg/semana. En 262 pacientes con DGH con datos a 4 años, la velocidad media (IC 95%) de crecimiento fue 4,3 (4,1 a 4,6) cm/año al inicio; 9,0 (8,7 a 9,4) cm/año tras un año y 5,5 (5,2 a 5,8) cm/año a los 4 años. La puntuación de desviación estándar (SDS) de talla fue -2,48 (-2,58 a -2,38) al inicio y -1,18 (-1,28 a -1,08) a los 4 años. La SDS de talla final menos la SDS de talla diana (n=241) fue -0,09 (-0,20 a 0,02). De 1.143 pacientes tratados con GH con seguimiento ≥1 año, 93 (8,1%) comunicaron acontecimientos adversos surgidos durante el tratamiento. En 7 niños se comunicaron acontecimientos adversos graves, que en 2 casos se consideraron posiblemente relacionados con GH. CONCLUSIÓN: La terapia de sustitución con GH fue efectiva para el aumento de talla en los pacientes españoles. El perfil de seguridad fue acorde con el ya conocido para el fármaco

INTRODUCTION: Country-specific information on pediatric GH therapy is available from multi-national studies. METHODS: A total of 1294 children in Spain enrolled in the observational Genetics and Neuroendocrinology of Short-stature International Study (GeNeSIS). Adverse events were assessed in all GH-treated patients (n=1267) and effectiveness in those with GH deficiency (GHD, 78%). RESULTS: Mean age at time of entry to the study was 9.8 years. GH was initiated at a median (Q1-Q3) 0.22 (0.20−0.25) mg/kg/week and administered for 2.8 (1.6-4.4) years. For 262 patients with GHD and 4-year data, mean (95% CI) height velocity was 4.3 (4.1 - 4.6) cm/year at baseline, 9.0 (8.7 to 9.4) cm/year at 1-year, and 5.5 (5.2 to 5.8) cm/year at 4-years. Height standard deviation score (SDS) was -2.48 (-2.58 to -2.38) at baseline and -1.18 (-1.28 to -1.08) at 4 years. Final height SDS minus target height SDS (n=241) was −0.09 (−0.20 to 0.02). In 1143 GH-treated patients with ≥1 year follow-up, 93 (8.1%) reported treatment-emergent adverse events. Serious events were reported for 7 children, with 2 considered GH-related. CONCLUSION: These data confirm the benefit of GH replacement therapy on height gain for the patients in Spain. The safety profile was consistent with that already known for GH therapy

Neuroendocrinology of the hair follicle: principles and clinical perspectives.

The human hair follicle (HF) is an exquisitely hormone-sensitive mini-organ that undergoes cyclical remodeling. It is also a source and target of numerous neurohormones, neuropeptides, and neurotransmitters that regulate HF growth, pigmentation, remodeling, immune status, stem cell biology, and energy metabolism. Indeed, organ-cultured human scalp HFs can be utilized to identify 'novel' clinically relevant functions of major neuromediators. This is pertinently illustrated by the discoveries of: (i) thyrotropin-releasing hormone (TRH) as a hair growth and pigmentation stimulator; (ii) TRH and thyrotropin (TSH) as potent promoters of mitochondrial activity and regulators of keratin expression; and (iii) prolactin as an epithelial stem cell modulator. Thus, HF neuroendocrinology affords insights well beyond hair growth and dermatoendocrinology, uncovering new translationally relevant neuroendocrinology principles and novel therapeutic targets.