Nonalcoholic fatty liver disease (NAFLD) spans steatosis through nonalcoholic steatohepatis, cirrhosis, and hepatocellular carcinoma (HCC) associated with striking systemic features and excess cardiovascular and liver-related mortality The pathogenesis of NAFLD is complex and multifactorial Endocrine derangements are closely linked with dysmetabolic traits For example, in animal and human studies, female sex is protected from dysmetabolism thanks to young individuals' ability to partition fatty acids towards ketone body production rather than very low density lipoprotein (VLDL)-triacylglycerol, and to sex-specific browning of white adipose tissue Ovarian senescence facilitates both the development of massive hepatic steatosis and the fibrotic progression of liver disease in an experimental overfed zebrafish model Consistently, estrogen deficiency, by potentiating hepatic inflammatory changes, hastens the progression of disease in a dietary model of nonalcoholic steatohepatitis (NASH) developing in ovariectomized mice fed a high-fat diet In humans, NAFLD more often affects men; and premenopausal women are equally protected from developing NAFLD as they are from cardiovascular disease It would be expected that early menarche, definitely associated with estrogen activation, would produce protection against the risk of NAFLD Nevertheless, it has been suggested that early menarche may confer an increased risk of NAFLD in adulthood, excess adiposity being the primary culprit of this association Fertile age may be associated with more severe hepatocyte injury and inflammation, but also with a decreased risk of liver fibrosis compared to men and postmenopausal status Later in life, ovarian senescence is strongly associated with severe steatosis and fibrosing NASH, which may occur in postmenopausal women Estrogen deficiency is deemed to be responsible for these findings via the development of postmenopausal metabolic syndrome Estrogen supplementation may at least theoretically protect from NAFLD development and progression, as suggested by some studies exploring the effect of hormonal replacement therapy on postmenopausal women, but the variable impact of different sex hormones in NAFLD (ie, the pro-inflammatory effect of progesterone) should be carefully considered

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NAFLD as a Sexual Dimorphic Disease: Role of Gender and Reproductive Status in the Development and Progression of Nonalcoholic Fatty Liver Disease and Inherent Cardiovascular Risk.

The skin is considered the mirror of the soul and is affected by neurohormonal triggers, especially stress. Hair follicles, keratinocytes, mast cells, melanocytes, and sebocytes all express sex and stress hormones implicating them in a local "hypothalamic-pituitary-adrenal axis." In particular, the peptides corticotropin-releasing hormone (CRH) and neurotensin (NT) have synergistic action stimulating mast cells and are uniquely elevated in the serum of patients with skin diseases exacerbated by stress. Addressing the neurohormonal regulation of skin function could lead to new targets for effective treatment of inflammatory skin diseases.

Neuroendocrinology of the skin

The Neuroendocrinology of the Microbiota-Gut-Brain Axis: A Behavioural Perspective.

The hypothalamic–pituitary–gonadal axis is of relevance in many processes related to the development, maturation and ageing of the male. Through this axis, a cascade of coordinated activities is carried out leading to sustained testicular endocrine function, with gonadal testosterone production, as well as exocrine function, with spermatogenesis. Conditions impairing the hypothalamic–pituitary–gonadal axis during paediatric or pubertal life may result in delayed puberty. Late-onset hypogonadism is a clinical condition in the ageing male combining low concentrations of circulating testosterone and specific symptoms associated with impaired hormone production. Testosterone therapy for congenital forms of hypogonadism must be lifelong, whereas testosterone treatment of late-onset hypogonadism remains a matter of debate because of unclear indications for replacement, uncertain efficacy and potential risks. This Primer focuses on a reappraisal of the physiological role of testosterone, with emphasis on the critical interpretation of the hypogonadal conditions throughout the lifespan of the male individual, with the exception of hypogonadal states resulting from congenital disorders of sex development. Male hypogonadism is a disorder associated with low testosterone levels and impaired spermatogenesis. The condition can arise from inherent defects in the testes or abnormalities in the regulation of testosterone secretion at the hypothalamic or pituitary level. This Primer summarizes the conditions that can lead to hypogonadism in boys and men.

Paediatric and adult-onset male hypogonadism

Infertility is defined as the inability of couples to have a baby after one year of regular unprotected intercourse, affecting 10 to 15% of couples. According to the latest WHO statistics, approximately 50-80 million people worldwide sufer from infertility, and male factors are responsible for approximately 20-30% of all infertility cases. The diagnosis of infertility in men is mainly based on semen analysis. The main parameters of semen include: concentration, appearance and motility of sperm. Causes of infertility in men include a variety of things including hormonal disorders, physical problems, lifestyle problems, psychological issues, sex problems, chromosomal abnormalities and single-gene defects. Despite numerous efforts by researchers to identify the underlying causes of male infertility, about 70% of cases remain unknown. These statistics show a lack of understanding of the mechanisms involved in male infertility. This article focuses on the histology of testicular tissue samples, the male reproductive structure, factors affecting male infertility, strategies available to find genes involved in infertility, existing therapeutic methods for male infertility, and sperm recovery in infertile men.

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Some of the Factors Involved in Male Infertility: A Prospective Review

Physiology of the Hypothalamic Pituitary Gonadal Axis in the Male.

Systemic Mastocytosis (SM) is characterized by accumulation of clonal, neoplastic proliferations of abnormal mast cells (MC) in one or more organ system other than skin. Presence of these multifocal clusters of abnormal mast cells is an essential feature of SM. Frequently associated with D816V (KIT) mutation, the presence of this mutation and elevated serum tryptase are minor criteria for diagnosis. SM manifestations depend on the degree of mast cell proliferation, activation and degranulation. SM has a variable prognosis and presentation, from indolent to "smoldering" to life-threatening disease. Bone manifestations of SM include: osteopenia with or without lytic lesions, osteoporosis with or without atraumatic fracture, osteosclerosis with increased bone density, and isolated lytic lesions. Male sex, older age, higher bone resorption markers, lower DKK1 level, lower BMD, absence of urticaria pigmentosa, and alcohol intake are all associated with increased risk of fracture. Treatment of SM is generally palliative. Most therapy is symptom-directed; and, infrequently, chemotherapy for refractory symptoms is indicated. Anti-histamines may alleviate direct bone effects of histamine. Bisphosphonates, including alendronate, clodronate, pamidronate and zoledronic acid are recommended as a first line treatment of SM and osteoporosis. Interferon α may act synergistically with bisphosphonates. As elevation of RANKL and OPG is reported in SM, denosumab could be an effective therapy for bone manifestations of SM.

Endocrine manifestations of systemic mastocytosis in bone.

Triglyceride Treatment in the Age of Cholesterol Reduction.

Serum testosterone concentrations decrease as men age. The age-related decline in testosterone levels, confirmed in several studies, results from defects in both testicular and hypothalamic-pituitary function. In some cases, it is unclear whether coexisting nonspecific signs and symptoms, such as decreases in energy and muscle mass, are a consequence of the age-related decline in endogenous testosterone or whether they are a result of other factors, such as coexisting conditions, concomitant medications, or perhaps aging itself. There is a widespread belief that undesirable changes in body composition and sexual dysfunction in men with hypogonadism are due to androgen deficiency. However, studies have shown that the amount of testosterone required to maintain lean mass, fat mass, strength, and sexual function varies widely in men. Therefore, benefits of raising testosterone levels in older men have not been established. In addition, metabolic and cardiovascular benefits or risks from testosterone therapy are still being debated.

Patricia Freitas Corradi

Papers

Physiology of the Hypothalamic Pituitary Gonadal Axis in the Male.

Endocrine manifestations of systemic mastocytosis in bone.

Triglyceride Treatment in the Age of Cholesterol Reduction.

Management of Testosterone Deficiency in the Aging Male

Dyslipidemia: Pathogenesis and Management