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Hypopituitarism refers to deficiency of one or more hormones produced by the anterior pituitary or released from the posterior pituitary. Hypopituitarism is associated with excess mortality, a key risk factor being cortisol deficiency due to adrenocorticotropic hormone (ACTH) deficiency. Onset can be acute or insidious, and the most common cause in adulthood is a pituitary adenoma, or treatment with pituitary surgery or radiotherapy. Hypopituitarism is diagnosed based on baseline blood sampling for thyroid stimulating hormone, gonadotropin, and prolactin deficiencies, whereas for ACTH, growth hormone, and antidiuretic hormone deficiency dynamic stimulation tests are usually needed. Repeated pituitary function assessment at regular intervals is needed for diagnosis of the predictable but slowly evolving forms of hypopituitarism. Replacement treatment exists in the form of thyroxine, hydrocortisone, sex steroids, growth hormone, and desmopressin. If onset is acute, cortisol deficiency should be replaced first. Modifications in replacement treatment are needed during the transition from paediatric to adult endocrine care, and during pregnancy.

A eubiotic microbiota influences many physiological processes in the metazoan host, including development and intestinal homeostasis. Here, we have shown that the intestinal microbiota modulates inflammatory responses caused by sex steroid deficiency, leading to trabecular bone loss. In murine models, sex steroid deficiency increased gut permeability, expanded Th17 cells, and upregulated the osteoclastogenic cytokines TNFα (TNF), RANKL, and IL-17 in the small intestine and the BM. In germ-free (GF) mice, sex steroid deficiency failed to increase osteoclastogenic cytokine production, stimulate bone resorption, and cause trabecular bone loss, demonstrating that the gut microbiota is central in sex steroid deficiency-induced trabecular bone loss. Furthermore, we demonstrated that twice-weekly treatment of sex steroid-deficient mice with the probiotics Lactobacillus rhamnosus GG (LGG) or the commercially available probiotic supplement VSL#3 reduces gut permeability, dampens intestinal and BM inflammation, and completely protects against bone loss. In contrast, supplementation with a nonprobiotic strain of E. coli or a mutant LGG was not protective. Together, these data highlight the role that the gut luminal microbiota and increased gut permeability play in triggering inflammatory pathways that are critical for inducing bone loss in sex steroid-deficient mice. Our data further suggest that probiotics that decrease gut permeability have potential as a therapeutic strategy for postmenopausal osteoporosis.

Key Points The pathogenesis of primary osteoporosis is complex and influenced by both environmental and genetic factors Oxidative stress, apoptosis, sex-steroid deficiency and macroautophagy are age-related risk factors that contribute to the pathogenesis of osteoporosis Lifestyle-related factors, such as inadequate intake of calcium and vitamin D, physical inactivity, smoking and excessive alcohol consumption are important risk factors for osteoporosis Mutations in several genes can cause different monogenic disorders characterized by decreased bone mineral density and increased bone fragility The contribution of genetic factors to polygenic osteoporosis is determined by the presence of variants in many genes, each with a small effect size This article discusses the many heritable and nonheritable factors contributing to primary osteoporosis, focusing on osteogenesis imperfecta, juvenile osteoporosis and other monogenic disorders associated with increased bone fragility. Understanding these conditions not only illuminates the pathogenesis of osteoporosis, but could also lead to the discovery of new therapeutic targets. Osteoporosis is a common disorder, affecting hundreds of millions of people worldwide, and characterized by decreased bone mineral density and increased fracture risk. Known nonheritable risk factors for primary osteoporosis include advanced age, sex-steroid deficiency and increased oxidative stress. Age is a nonmodifiable risk factor, but the influence of a person's lifestyle (diet and physical activity) on their bone structure and density is modifiable to some extent. Heritable factors influencing bone fragility can be monogenic or polygenic. Osteogenesis imperfecta, juvenile osteoporosis and syndromes of decreased bone density are discussed as examples of monogenic disorders associated with bone fragility. So far, the factors associated with polygenic osteoporosis have been investigated mainly in genome-wide association studies. However, epigenetic mechanisms also contribute to the heritability of polygenic osteoporosis. Identification of these heritable and nonheritable risk factors has already led to the discovery of therapeutic targets for osteoporosis, which emphasizes the importance of research into the pathogenetic mechanisms of osteoporosis. Accordingly, this article discusses the many heritable and nonheritable factors that contribute to the pathogenesis of primary osteoporosis. Although osteoporosis can also develop secondary to many other diseases or their treatment, a discussion of the factors that contribute only to secondary osteoporosis is beyond the scope of this Review.

Osteoporosis develops with high prevalence in both postmenopausal women and hypogonadal men. Osteoporosis results in significant morbidity, but no cure has been established. Mesenchymal stem cells (MSCs) critically contribute to bone homeostasis and possess potent immunomodulatory/anti-inflammatory capability. Here, we investigated the therapeutic efficacy of using an infusion of MSCs to treat sex hormone-deficient bone loss and its underlying mechanisms. In particular, we compared the impacts of MSC cytotherapy in the two genders with the aim of examining potential gender differences. Using the gonadectomy (GNX) model, we confirmed that the osteoporotic phenotypes were substantially consistent between female and male mice. Importantly, systemic MSC transplantation (MSCT) not only rescued trabecular bone loss in GNX mice but also restored cortical bone mass and bone quality. Unexpectedly, no differences were detected between the genders. Furthermore, MSCT demonstrated an equal efficiency in rectifying the bone remodeling balance in both genders of GNX animals, as proven by the comparable recovery of bone formation and parallel normalization of bone resorption. Mechanistically, using green fluorescent protein (GFP)-based cell-tracing, we demonstrated rapid engraftment but poor inhabitation of donor MSCs in the GNX recipient bone marrow of each gender. Alternatively, MSCT uniformly reduced the CD3 + T-cell population and suppressed the serum levels of inflammatory cytokines in reversing female and male GNX osteoporosis, which was attributed to the ability of the MSC to induce T-cell apoptosis. Immunosuppression in the microenvironment eventually led to functional recovery of endogenous MSCs, which resulted in restored osteogenesis and normalized behavior to modulate osteoclastogenesis. Collectively, these data revealed recipient sexually monomorphic responses to MSC therapy in gonadal steroid deficiency-induced osteoporosis via immunosuppression/anti-inflammation and resident stem cell recovery. Osteoporosis: Stem cell therapy success for both sexes Stem cell therapy shows promise in reversing the bone loss caused by sex hormone deficiency in male and female mice. Adult stem cells, known as mesenchymal stem cells (MSCs), have been shown to facilitate bone healing when administered into the caudal vein of mice. Yan Jin and Cheng-Hu Hu at Fourth Military Medical University in Xi’an, China, and co-workers investigated the efficacy of MSC-based therapy in treating osteoporosis triggered by the loss of sex hormones. They generated mouse models with sex hormone deficiencies, and showed that the resulting osteoporosis seen was remarkably similar in males and females. MSC transplantation resulted in the restoration of bone formation and bone resorption processes in both sexes. The transplanted MSCs also suppressed the inflammation associated with osteoporosis, allowing resident MSC populations in the bone marrow to recover bone damage.

Recent evidence suggests that the decline in resistance to viral infections with age occurs predominantly as a result of a gradual loss of naïve antigen-specific T cells. As such, restoration of the naïve T cell repertoire to levels seen in young healthy adults may improve defence against infection in the aged. We have previously shown that sex steroid ablation (SSA) rejuvenates the ageing thymus and increases thymic export of naïve T cells, but it remains unclear whether T cell responses are improved. Using mouse models of clinically relevant diseases, we now demonstrate that SSA increases the number of naïve T cells able to respond to antigen, thereby enhancing effector responses in aged mice. Specifically, aged mice exhibit a delay in clearing influenza A virus, which correlates with diminished specific cytotoxic activity. This is due to a decreased magnitude of response and not an intrinsic defect in effector T cell function. Upon SSA, aged mice exhibit increased T cell responsiveness that restores efficient viral clearance. We further demonstrate that SSA decreases the incidence of an inducible tumour in aged mice and can potentially increase their responsiveness to a low-dose human papillomavirus vaccine in clearing pre-formed tumours. As thymectomy abrogates the increase in T cell numbers and responsiveness following SSA, we propose that the T cell effects of SSA are dependent on thymic reactivation and subsequent replenishment of the peripheral T cell pool with newly emigrated naïve T cells. These findings have important implications for strategies to improve protection from infection and responsiveness to vaccination in the aged.

Cancer survivors often experience symptoms related to hormone deprivation, including vasomotor symptoms, genitourinary symptoms, and sexual health concerns. These symptoms can occur due to natural menopause in midlife women, or they can be brought on by oncologic therapies in younger women or men. We searched PubMed for English-language studies from January 1990 through January 2016 to identify relevant articles on the management of hormone deprivation symptoms, including vasomotor, genitourinary, and sexual symptoms in patients with cancer. The search terms used included hormone deprivation, vasomotor symptoms, hot flash, vaginal dryness, sexual dysfunction, and breast cancer. This manuscript provides a comprehensive description of data supporting the treatment of symptoms associated with hormone deprivation.

Slow delayed rectifier potassium current (I Ks ) is important in action potential (AP) repolarization and repolarization reserve. We tested the hypothesis that there are sex-specific differences in I Ks , AP, and their regulation by β-adrenergic receptors (β-AR’s) using whole-cell patch-clamp. AP duration (APD 90 ) was significantly longer in control female (F) than in control male (M) myocytes. Isoproterenol (ISO, 500 nM) shortened APD 90 comparably in M and F, and was largely reversed by β 1 -AR blocker CGP 20712A (CGP, 300 nM). Inhibition of I Ks with chromanol 293B (10 μM) resulted in less APD prolongation in F at baseline (3.0 vs 8.9 %, p  < 0.05 vs M) and even in the presence of ISO (5.4 vs 20.9 %, p  < 0.05). This suggests that much of the ISO-induced APD abbreviation in F is independent of I Ks . In F, baseline I Ks was 42 % less and was more weakly activated by ISO (19 vs 68 % in M, p  < 0.01). ISO enhancement of I Ks was comparably attenuated by CGP in M and F. After ovariectomy, I Ks in F had greater enhancement by ISO (72 %), now comparable to control M. After orchiectomy, I Ks in M was only slightly enhanced by ISO (23 %), comparable to control F. Pretreatment with thapsigargin (to block SR Ca release) had bigger impact on ISO-induced APD shortening in F than that in M ( p  < 0.01). In conclusion, we found that there are sex differences in I Ks , AP, and their regulation by β-AR’s that are modulated by sex hormones, suggesting the potential for sex-specific antiarrhythmic therapy.

Chronic heart failure (CHF) represents a debilitating condition with morbidity and mortality comparable to other end-stage disease states. 1 Non-oedematous weight loss in the context of chronic heart failure is associated with adverse prognosis, as it is a strong independent risk factor for mortality in patients with CHF and cachexia: patients with CHF with wasting have a mortality at 18 months as high as 50% compared to 17% in those without cachexia. 2 A number of different mediators have been implicated in the wasting process, including activation of pro-inflammatory cytokines, secretion of neurohormones and peptides, including PYY, ghrelin, leptin, growth hormone and insulin, and a relative deficiency of micronutrients and macronutrients. 3 It has been suggested that a low testosterone level may represent one of the factors contributing to the anabolic/catabolic imbalance characteristically present in many patients with advanced CHF. 4 In the study by Guder et al (see page 504 ) total (TT) and free serum testosterone (FT), dehydroepiandrosterone sulfate (DHEAS), and sex hormone binding globulin (SHBG) were studied in a cohort of 191 patients with heart failure (mean age 64 years; NYHA class I-IV 24/35/35/6%). Longitudinal data suggest that total testosterone, free and bioavailable testosterone and DHEAS decline with age, while SHBG increases. 8 Prospective population-based studies have shown a role of testosterone in predicting mortality in healthy individuals. 9 10 On the other hand, androgen deficiency is known to occur in several chronic disorders and evidence on the benefit of substitution therapy often not found. 11 Correcting sex steroid axes in chronic heart failure has largely concentrated on testosterone replacement.

Introduction The molecular and cellular interactions between the immune system and bone tissue have been established. Sex hormone deficiency after menopause has multifunctional role by influencing growth, differentiation, and metabolism of the skeletal and the immune system. Discussion We have used nonparametric and multidimensional expression pattern analyses to determine significantly changed mRNA profile of immune system-associated genes in postmenopausal (POST) and premenopausal (PRE) nonosteoporotic bone. Ten bone tissue samples from POST patients and six bone tissue samples from PRE women were examined in our study. The transcription differences of the selected 50 genes were analyzed in TaqMan probe-based quantitative real-time reverse transcriptase polymerase chain reaction system. Mann-Whitney test indicated significantly downregulated transcription activity of three genes (CD14, HLA-A/MHCI, ITGAM/CD11b) and upregulated expression of six genes (C3, CD86/B7-2, IL-10, IL-6, TGFB3, TNFSF11/RANKL) in postmenopausal bone. According to the canonical variate analysis results, the groups of POST and PRE women are separable by genes coding for cytokines, costimulator molecules, and cell surface receptors involved in antigen presentation and T cell stimulation processes which have high discriminatory power. Based on a complex gene expression pattern analysis of human bone tissue, we could distinguish POST and PRE states from an immunological aspect. Our data might provide further insight into the changes of the intersystem crosstalk between immune and skeletal homeostasis, as well as local immune response in the altered microenvironment of postmenopausal bone.