Hormonal Dysfunction in Male Infertility -Diagnosis and Treatment !

Male Infertility:

Treatment of infertility-related hormonal dysfunction in men requires an understanding of the hormonal basis of spermatogenesis. The best method for accurately determining male androgenization status remains elusive. Treatment of hormonal dysfunction can fall into two categories — empirical and targeted. Empirical therapy refers to experience-based treatment approaches in the absence of an identifiable etiology. Targeted therapy refers to the correction of a specific underlying hormonal abnormality.

Since the first case reports in 1910 of testicular atrophy after canine hypophysectomy, the hormonal basis of human reproduction has been an area of evolving investigation. An array of treatment modalities are available for hormonal dysfunction in the setting of male infertility, but the diagnosis of such dysfunction and its treatment is often empirical, or guided by the clinician's judgement, and can be open to interpretation. Our ability to understand the intra testicular hormonal environment and its effect on spermatogenesis is limited by current methods of routine clinical investigation.

Investigations into female infertility benefit from reliance on objective, verifiable outcomes such as ovulation, biochemical pregnancy, and clinical pregnancy. Meanwhile, the male counterpart has been hampered by the necessary dependence on bulk seminal parameters, which are notoriously poor predictors of fertility potential. Perhaps the only truly reliable semen analysis is one indicating azoospermia and that is where the most exciting clinical outcomes research has focused.

This review article describes and discusses the pathophysiology, diagnosis, and treatment of fertility-associated male hormonal dysfunction.

• Oestradiol is the principal mediator of negative feedback on the hypothalamic–pituitary axis, which illustrates the influence of selective oestrogen receptor modulators and aromatase inhibitors on male hormonal parameters

• Serum hormonal assays are unreliable indicators of intratesticular androgen levels, and the best approach for determining male androgen status remains elusive

• Follicle-stimulating hormone and inhibin B are markers of spermatogenesis and their relative values in the setting of an intact hypothalamic–pituitary–gonadal axis provide important information about testicular function

• Targeted hormonal therapy corrects specific hormonal dysfunctions, empirical hormonal therapy is employed when no underlying cause is identified and the evidence for empirical therapy is dependent on the type of medication used

• A return of sperm to the ejaculate or successful surgical sperm retrieval among men with azoospermia owing to spermatogenic dysfunction are the most objective indicators of outcomes of hormonal therapy

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A Primeview on Sickle Cell Disease !

Primeview:

Sickle cell disease (SCD) is a group of inherited disorders caused by mutations in HBB, which encodes haemoglobin subunit β. Haemoglobin molecules that include mutant sickle β-globin subunits can polymerize; erythrocytes that contain mostly haemoglobin polymers assume a sickled form and are prone to haemolysis. Other pathophysiological mechanisms that contribute to the SCD phenotype are vaso-occlusion and activation of the immune system. SCD is characterized by a remarkable phenotypic complexity. Common acute complications are acute pain events, acute chest syndrome and stroke; chronic complications (including chronic kidney disease) can damage all organs. Hydroxycarbamide, blood transfusions and haematopoietic stem cell transplantation can reduce the severity of the disease. Early diagnosis is crucial to improve survival, and universal newborn screening programmes have been implemented in some countries but are challenging in low-income, high-burden settings.

Sickle cell disease (SCD) is an umbrella term that defines a group of inherited diseases (including sickle cell anaemia (SCA), HbSC and HbSβ-thalassaemia) characterized by mutations in the gene encoding the haemoglobin subunit β (HBB). Haemoglobin (Hb) is a tetrameric protein composed of different combinations of globin subunits; each globin subunit is associated with the cofactor haem, which can carry a molecule of oxygen. Hb is expressed by red blood cells, both reticulocytes (immature red blood cells) and erythrocytes (mature red blood cells). Several genes encode different types of globin proteins, and their various tetrameric combinations generate multiple types of Hb, which are normally expressed at different stages of life — embryonic, fetal and adult. Hb A (HbA), the most abundant (>90%) form of adult Hb, comprises two α-globin subunits (encoded by the duplicated HBA1 and HBA2 genes) and two β-globin subunits.

A single nucleotide substitution in HBB results in the sickle Hb (HbS) allele βS; the mutant protein generated from the βS allele is the sickle β-globin subunit and has an amino acid substitution. Under conditions of deoxygenation (that is, when the Hb is not bound to oxygen), Hb tetramers that include two of these mutant sickle β-globin subunits (that is, HbS) can polymerize and cause the erythrocytes to assume a crescent or sickled shape from which the disease takes its name. Hb tetramers with one sickle β-globin subunit can also polymerize, albeit not as efficiently as HbS. Sickle erythrocytes can lead to recurrent vaso-occlusive episodes that are the hallmark of SCD. SCD is inherited as an autosomal codominant trait; individuals who are heterozygous for the βS allele carry the sickle cell trait (HbAS) but do not have SCD, whereas individuals who are homozygous for the βS allele have SCA. SCA, the most common form of SCD, is a lifelong disease characterized by chronic haemolytic anaemia, unpredictable episodes of pain and widespread organ damage.

This primeview focuses on SCA and aims to balance such remarkable advances with the key major challenges remaining worldwide to improve the prevention and management of this chronic disease and ultimately to discover an affordable cure.

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Molecular Basis of Tolerance and Immunity to Antigens.

Molecular Immunology

The intestinal immune system has to discriminate between harmful and beneficial antigens. Although strong protective immunity is essential to prevent invasion by pathogens, equivalent responses against dietary proteins or commensal bacteria can lead to chronic disease. These responses are normally prevented by a complex interplay of regulatory mechanisms. This article reviews the unique aspects of the local microenvironment of the intestinal immune system and discuss how these promote the development of regulatory responses that ensure the maintenance of homeostasis in the gut.

The intestinal immune system is the largest and most complex part of the immune system. Not only does it encounter more antigen than any other part of the body, but it must also discriminate clearly between invasive organisms and harmless antigens, such as food proteins and commensal bacteria. Most human pathogens enter the body through a mucosal surface, such as the intestine, and strong immune responses are required to protect this physiologically essential tissue. In addition, it is important to prevent further dissemination of such infections. By contrast, active immunity against non-pathogenic materials would be wasteful, and hypersensitivity responses against dietary antigens or commensal bacteria can lead to inflammatory disorders such as Coeliac Disease and Crohn's Disease, respectively. As a result, the usual response to harmless gut antigens is the induction of local and systemic immunological tolerance, known as oral tolerance. In addition to its physiological importance, this phenomenon can be exploited for the immunotherapy of autoimmune and inflammatory diseases, but it is also an obstacle to the development of recombinant oral vaccines. For these reasons, there is great interest in the processes that determine the immunological consequences of oral administration of antigen. To some extent, this discrimination between harmful and harmless antigens also occurs in other parts of the immune system, as it partly results from inherent properties of the antigen and associated adjuvants. Nevertheless, it has been proposed that there are also specific features of mucosal tissues that favour the induction of tolerance, the production of immunoglobulin A antibodies and, to a lesser extent, T helper 2 (TH2)-cell responses. Several features of mucosal tissues might contribute to these effects, including a unique ontogeny and anatomical patterning, specialized cells and organs that are involved in the uptake of antigen, distinctive subsets of antigen-presenting cells (APCs) and several unusual populations of B and T cells. In addition, the migration of lymphocytes to the intestine is controlled by a series of unique adhesion molecules and chemokine receptors.

This review article discusses the anatomical factors which determine the special nature of small intestinal immune responses, and the unique processes and cells involved in the uptake and presentation of antigen to T cells in the gut. In particular, it focuses on the local factors that determine the behaviour of APCs and T cells in the gut and discuss recent evidence that challenges the conventional dogma that Peyer’s patches are the only site for the initiation of mucosal immunity and tolerance.

It also focuses on the small intestine, as this tissue has been studied in most detail and it contains the largest proportion of immune cells in the gut. However, the reader should be aware that each compartment of the intestine, from the oropharynx to the stomach and to the rectum, has its own specializations, which might have individual effects on immune regulation in response to local antigens.

• The intestinal immune system is an anatomically and functionally distinct compartment, in which a careful distinction must be made between harmful antigens, such as invasive pathogens, and harmless antigens, such as dietary proteins or commensal bacteria.

• The default response to harmless antigens is the induction of tolerance. A breakdown in this physiological process can lead to disease.

• Immune responses and tolerance in the gut are initiated in organized lymphoid organs, such as the Peyer's patches and mesenteric lymph nodes (MLNs). The mucosa contains effector or regulatory cells that migrate there selectively, from the MLNs, in the lymph and bloodstream under the control of α4β7 integrins and the chemokine receptor CCR9.

• Pathogens might enter the intestinal immune system through M cells in the follicle-associated epithelium of the Peyer's patches, whereas soluble antigens might gain access predominantly through the normal epithelium that covers the villus mucosa.

• Peyer's patches, lamina propria and MLNs contain unusual populations of dendritic cells (DCs), some of which are characterized by the production of interleukin-10 (IL-10) and which polarize T cells to an IL-4-, IL-10- and transforming growth factor-β (TGF-β)-producing 'regulatory' phenotype.

• Genetically determined factors, together with luminal bacteria, might act on epithelial and stromal components of the intestinal mucosa to produce a local microenvironment that is dominated by the constitutive production of prostaglandin E2 (PGE2), TGF-β and IL-10. Under physiological conditions, this favours the differentiation of regulatory DCs and T cells, which leads to systemic tolerance and/or immunoglobulin-A production.

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Cutaneous Leishmaniasis: Immune Responses in Protection and Pathogenesis.

Immunology

Cutaneous leishmaniasis is a major public health problem and causes a range of diseases from self-healing infections to chronic disfiguring disease. Currently, there is no vaccine for leishmaniasis, and drug therapy is often ineffective. Since the discovery of CD4+ T helper 1 (TH1) cells and TH2 cells 30 years ago, studies of cutaneous leishmaniasis in mice have answered basic immunological questions concerning the development and maintenance of CD4+ T cell subsets. However, new strategies for controlling the human disease have not been forthcoming. Nevertheless, advances in our knowledge of the cells that participate in protection against Leishmania infection and the cells that mediate increased pathology have highlighted new approaches for vaccine development and immunotherapy. In this Review, we discuss the early events associated with infection, the CD4+ T cells that mediate protective immunity and the pathological role that CD8+ T cells can have in cutaneous leishmaniasis.

Cutaneous leishmaniasis — which is caused by several protozoal parasites of the genus Leishmania — is endemic to South and Central America, Northern Africa, the Middle East and parts of Asia, and an estimated 1 million new cases arise each year. Of particular interest to immunologists is the wide range of clinical manifestations associated with this disease, which, similar to tuberculosis and leprosy, is dictated largely by the type and magnitude of the immune response of the host. As in most infections, the immune response to cutaneous leishmaniasis depends on many host factors, as well as on the differences between the infecting Leishmania spp. Experimental infections in mice also exhibit a spectrum of clinical presentations depending on the mouse strain and the infecting parasite species or strain used.

• Cutaneous leishmaniasis exhibits a wide spectrum of clinical presentations that is determined largely by the host immune response. The host immune response to infection is influenced both by host genetics and the Leishmania spp. and/or strain.
• The rapid recruitment of neutrophils and inflammatory monocytes following infection with Leishmania influences the course of disease. Neutrophils can have both protective and deleterious roles, whereas inflammatory monocytes kill Leishmania parasites and differentiate into monocyte-derived dendritic cells that promote the development of protective CD4+ T helper 1 (TH1) cells.
• Control of Leishmania infection depends on the production of interferon-γ by CD4+ TH1 cells, which leads to enhanced killing by macrophages due to the production of reactive oxygen species and nitric oxide.
• CD8+ T cells recruited to Leishmania lesions exhibit a cytolytic profile and lyse infected cells without killing the parasites, which leads to enhanced inflammation and increased severity of disease. Controlling these pathogenic CD8+ T cells, or the downstream mediators of inflammation that they induce, is a new approach to leishmaniasis immunotherapy.
• Infection with Leishmania generates several types of CD4+ T cells that mediate resistance to reinfection, including effector T cells, effector memory T cells, central memory T cells and tissue-resident memory T cells. There is currently no Leishmania vaccine, and a hurdle for vaccine development is that the most effective T cells are short-lived effector T cells; targeting longer lived central memory and tissue-resident memory T cells is an alternative approach.

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Transcriptional Regulation by Mediator Complex

Gene Regulation

Alterations in the regulation of gene expression are frequently associated with developmental diseases or cancer. Transcription activation is a key phenomenon in the regulation of gene expression.

In all eukaryotes, mediator of RNA polymerase II transcription (Mediator), a large complex with modular organization, is generally required for transcription by RNA polymerase II, and it regulates various steps of this process. The main function of Mediator is to transduce signals from the transcription activators bound to enhancer regions to the transcription machinery, which is assembled at promoters as the preinitiation complex (PIC) to control transcription initiation.

Recent functional studies of Mediator with the use of structural biology approaches and functional genomics have revealed new insights into Mediator activity and its regulation during transcription initiation, including how Mediator is recruited to transcription regulatory regions and how it interacts and cooperates with PIC components to assist in PIC assembly.

Novel roles of Mediator in the control of gene expression have also been revealed by showing its connection to the nuclear pore and linking Mediator to the regulation of gene positioning in the nuclear space. Clear links between Mediator subunits and disease have also encouraged studies to explore targeting of this complex as a potential therapeutic approach in cancer and fungal infections.

Key points

• Recent structural advances based on improvements in electron microscopy methodology have enabled the generation of high-resolution structural models of the mediator of RNA polymerase II transcription (Mediator) complex and of the preinitiation complex (PIC) in the presence of Mediator.
• The module composition of Mediator changes between its recruitment to upstream regulatory regions (enhancers or upstream activating sequences where Mediator is bound to transcription factors) and its action on core promoters together with PIC components.
• The functional interplay between Mediator and general transcription factors in PIC assembly is closely related to chromatin architecture at promoter regions.
• Direct contact between Mediator and the nuclear pore-associated transcription-coupled export (TREX2) complex suggests that Mediator functions in gene positioning in the nuclear space.
• Mediator has been shown to function in the establishment of transcriptional memory, which also involves Mediator interactions with the nuclear pore.
• Potential therapeutic targeting and modulation of Mediator activity in cancers and in fungal infectious diseases emphasizes the importance of studies of Mediator mechanisms for improving human health.

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High-Sensitivity Assays for Troponin in Patients with Cardiac Disease !

Troponin is a widely used biomarker in patients with cardiac disease. The use of troponin is well established in patients with suspected acute myocardial infarction (AMI), but troponin measurement is also used in other acute and nonacute settings. In patients with suspected AMI, early decision-making is crucial to allow rapid treatment and further diagnostic evaluation. Current guidelines recommend serial measurements of troponin with a cut-off concentration at the 99th percentile to triage patients in the emergency department.

Newer, high-sensitivity assays for troponin enable the detection of distinctly lower concentrations. Using these assays and very low cut-off concentrations, several rapid diagnostic strategies have been reported to improve diagnosis in acute cardiac care. Furthermore, noncoronary and non-acute applications of troponin assays — for example as a biomarker in patients with heart failure, pulmonary embolism, or stable coronary artery disease — are on the horizon and might improve individual risk stratification.

In this Review, we provide an overview on the development of high-sensitivity assays for troponin, and their application in patients with cardiac disease.

Pathophysiological background of troponin and troponin release

in different settings. A schematic overview of myocardial structure

related to troponin (inset), as well as the plasma troponin concentrations 

in different clinical settings (young and healthy, elderly or chronic diseases,

myocardial injury, and myocardial infarction).

Read more: High-Sensitivity Assays for Troponin in Patients with Cardiac Disease !

Source: NatureReviewsCadiology

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The Theory of Disappearing Microbiota and the Epidemics of Chronic Diseases.

In the present era, medical scientists have been confounded by the increasing incidence of multiple diseases across the world, beginning first in developed countries, and gradually spreading to other areas as they develop. These include the rises in cases of obesity, asthma, hay fever, food allergies, inflammatory bowel disease, juvenile (type 1) diabetes and autism, among many others. Are these diseases, which affect different body systems, unrelated or can a unified theory explain the increased incidence of all of these?

I believe that the latter possibility is true, and that the central theory to explain why these diseases have arisen and by what mechanism is based on modern changes in early life events that are related to the human microbiome. According to this theory, the microbiome of humans and of other animals is not accidental, but has been selected over long time periods to optimize host reproductive success through interactions between the microbiota and host physiology. Early life is the crucial period during which the adult microbiome becomes established, and development of the host and of the microbiota occur together in a conjoined manner through a dynamic equilibrium that follows a well-choreographed path. In early life, the context is set for the important developmental decisions that are required for the immune system to distinguish between what is self and what is not self, for metabolic organs to partition how much energy to expend or to save, and for the brain to determine how to respond socially to a person who might be either a friend or a foe.

Read more: The theory of disappearing microbiota and the epidemics of chronic diseases

Figure 1: A model for the interaction of the inherited microbiota with
early life immunological development in past and present children.

Source: NATURE REVIEWS IMMUNOLOGY

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Heterogeneity in Tuberculosis.

Infection with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), results in a range of clinical presentations in humans. Most infections manifest as a clinically asymptomatic, contained state that is termed latent TB infection (LTBI); a smaller subset of infected individuals present with symptomatic, active TB. Within these two seemingly binary states, there is a spectrum of host outcomes that have varying symptoms, microbiologies, immune responses and pathologies. Recently, it has become apparent that there is diversity of infection even within a single individual. A good understanding of the heterogeneity that is intrinsic to TB — at both the population level and the individual level — is crucial to inform the development of intervention strategies that account for and target the unique, complex and independent nature of the local host–pathogen interactions that occur in this infection. In this Review, we draw on model systems and human data to discuss multiple facets of TB biology and their relationship to the overall heterogeneity observed in the human disease.

Read more: Heterogeneity in Tuberculosis.

Figure 1: A classical tuberculosis granuloma. The hallmark tuberculosis
granuloma is a highly organized collection of immune cells that aggregate
around a central necrotic core.

Source: NATURE REVIEWS IMMUNOLOGY

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The Mucosal Immune System: Master Regulator of Bidirectional Gut–Brain Communications

Communication between the brain and gut is not one-way, but a bidirectional highway whereby reciprocal signals between the two organ systems are exchanged to coordinate function. The messengers of this complex dialogue include neural, metabolic, endocrine and immune mediators responsive to diverse environmental cues, including nutrients and components of the intestinal microbiota (microbiota–gut–brain axis). We are now starting to understand how perturbation of these systems affects transition between health and disease. The pathological repercussions of disordered gut–brain dialogue are probably especially pertinent in functional gastrointestinal diseases, including IBS and functional dyspepsia. New insights into these pathways might lead to novel treatment strategies in these common gastrointestinal diseases. In this Review, we consider the role of the immune system as the gatekeeper and master regulator of brain–gut and gut–brain communications. Although adaptive immunity (T cells in particular) participates in this process, there is an emerging role for cells of the innate immune compartment (including innate lymphoid cells and cells of the mononuclear phagocyte system). We will also consider how these key immune cells interact with the specific components of the enteric and central nervous systems, and rapidly respond to environmental variables, including the microbiota, to alter gut homeostasis.

Key points

• Common gastrointestinal diseases, such as IBS, functional dyspepsia and IBD, are closely linked to psychological morbidity
• This link is driven in part through bidirectional signaling between the brain and gut, which reciprocally regulate each other
• Growing evidence implicates the importance of immune activation, which might be overt (IBD) or more subtle (IBS, functional dyspepsia) in pathological gut–brain interactions
• The composition of the intestinal microbiota affects behaviour and mood, which could in part rely on selective activation of distinct host cytokine responses
• Therapeutic targeting of gut microorganisms, host immunity or psychological symptoms could hold the key to uncoupling pathological interactions between the gut and brain

Read more: The Mucosal Immune System: Master Regulator of Bidirectional Gut–Brain Communications

Key brain–immune–gut interactions

Source: Nature Reviews: Gastroenterology & Hepatology