Non-alcoholic fatty liver disease through the female lifespan: the role of sex hormones.

The prevalence of non-alcoholic fatty liver disease (NAFLD) differs between various stages of the female lifespan. The aim of this review is to summarize current evidence on the association of NAFLD and circulating sex hormones and to explore the pathogenesis of NAFLD within the context of (1) sex hormone changes during the reproductive, post-reproductive female life and beyond and (2) the in vitro and in vivo evidence on pharmacological modulation in women on menopausal hormone treatment (MHT) or endocrine therapy after breast cancer. The fluctuation in estrogen concentrations, the relative androgen excess, and the age-related reduction in sex hormone-binding globulin are related to increased NAFLD risk. Moreover, the peri-menopausal changes in body composition and insulin resistance might contribute to the increased NAFLD risk. Whether MHT prevents or improves NAFLD in this population remains an open question. Studies in women with breast cancer treated with tamoxifen or non-steroidal aromatase inhibitors point to their adverse effects on NAFLD development, although a more pronounced effect of tamoxifen is reported. Future studies focusing on the underlying pathogenesis should identify subgroups with the highest risk of NAFLD development and progression into more aggressive forms, as well as elucidate the role of hormone therapies, such as MHT.

Premature ovarian insufficiency: a toolkit for the primary care physician.

Premature ovarian insufficiency (POI) refers to the loss of ovarian activity before the age of 40 years, which leads to hypoestrogenism and amenorrhea. The diagnosis of POI in a young woman has potentially life-changing physical and emotional consequences for both the patient and her family. Therefore, it is very important that the diagnosis is correct and that it is made in a timely manner. Unfortunately, the diagnosis and therefore the effective treatment of POI are often delayed, which underlines the need for education of the broad medical community on the issue. A panel of menopause experts reviewed and critically appraised the literature, and present: (1) the diagnostic approach to POI, (2) the investigation of the etiology of this condition, (3) the therapeutic strategy regarding both hormone replacement therapy and fertility, and (4) the long-term follow-up and management for ensuring quality of life, as well as urogenital, cardiovascular, bone and mental health. The ultimate goal of this article is to provide a complete toolkit for the primary care physician to have easy access to all the information needed for the optimal management of women with POI, in the context of evidence-based and personalized medicine.HIGHLIGHTSPremature ovarian insufficiency occurs in 1% of the female population of reproductive age, yet the diagnosis is often delayed, with severe physical and emotional consequences for the patient.Primary care physicians should be aware of the possibility of premature ovarian insufficiency in young women presenting with menstrual irregularity.Prompt initiation of hormone replacement therapy ensures quality of life and prevents osteoporosis and cardiovascular disease.Women seeking fertility should be referred to specialists to discuss assisted reproduction options.

How we treat endocrine complications of immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) are antibodies that target certain immune checkpoints (ICs), such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death 1 (PD-1) or its ligand (PD-L1), and have emerged as a powerful new tool for oncologists. As these immune checkpoints are crucial for immunological self-tolerance, such therapies can trigger autoimmune adverse effects. Endocrine complications are among the most common, including hypophysitis, thyroid dysfunction, diabetes mellitus and primary adrenal insufficiency, while autoimmune polyendocrine syndrome type 2 (APS-2) may also present. The aim of this article is to critically appraise the literature and present (i) the biological role and function of the main ICs, (ii) the use of ICIs in the treatment of various cancer types, (iii) the endocrine complications of cancer immunotherapy with ICIs and (iv) practical recommendations for screening and management of patients with such endocrinopathies in everyday clinical practice.

The role of sclerostin/dickkopf-1 and receptor activator of nuclear factor kB ligand/osteoprotegerin signalling pathways in the development of osteoporosis in patients with haemophilia A and B: A cross-sectional study.

AIM: Haemophilia A and B are associated with reduced bone mineral density (BMD). The aim of this study was to assess circulating sclerostin and dickkopf-1 (Dkk-1), (inhibitors of osteoblastic differentiation), as well as the receptor activator of nuclear factor kB ligand (RANKL)/osteoprotegerin (OPG) system (the major regulator of osteoclastogenesis), in patients with haemophilia (PWH), their possible correlations with clinical risk factors and the effect of ibandronate on these markers. METHODS: Eighty-nine male PWH (mean age 45.9 ± 15.3 years) and 30 age-matched healthy male controls participated. BMD was assessed by DXA. Sclerostin, Dkk-1, RANKL and OPG were measured in serum of patients, controls, as well as in ten patients receiving oral ibandronate (150 mg/mo), at baseline and after 12 months. RESULTS: Patients with haemophilia had lower circulating sclerostin (median ± IQR: 47.4 ± 26.93 vs 250 ± 250 pmol/L, P < .001), Dkk-1 (21.24 ± 17.18 vs 26.16 ± 15.32pg/mL, P = .04) and higher levels of RANKL (0.23 ± 0.03 vs 0.04 ± 0.03 pmol/L, P = .001), RANKL/OPG ratio (0.063 ± 0.25 vs 0.005 ± 0.11, P = .001) compared with controls. Patients with low BMD had higher OPG concentrations compared to those with normal BMD. Sclerostin and RANKL/OPG correlated positively with BMD. Patients with severe haemophilia had lower sclerostin concentrations compared with those with mild or moderate disease. The degree of arthropathy negatively correlated with sclerostin and Dkk-1 levels. PWH who received ibandronate showed a decrease in serum Dkk-1 without any significant effect on sclerostin and RANKL/OPG. CONCLUSIONS: Patients with haemophilia present increased osteoclastic activity coupled with compensatory increased osteoblastic activity. Ibandronate did not affect RANKL/OPG ratio, but it decreased Dkk-1.

Hypovitaminosis D in pregnancy in the Mediterranean region: a systematic review.

Despite high levels of sunshine, maternal hypovitaminosis D during pregnancy is prevalent in the Mediterranean region. The aim of this study is to systematically review trials that investigated vitamin D concentrations during pregnancy in this region, in order to determine predictors of hypovitaminosis D and explain this phenomenon. After applying inclusion/exclusion criteria, 15 studies were entered into the systematic review involving 2649 pregnant women and 820 neonates. The main outcome was maternal vitamin D status, assessed by serum 25-hydroxy-vitamin D (25(OH)D) concentrations. Possible predictors of the outcome included maternal age, body mass index (BMI), race, socioeconomic status, skin type, gestational age, sun exposure, calcium and vitamin D intake and supplementation, smoking status, parity and season of delivery. Studies differed widely in vitamin D deficiency criteria, method of measurement and outcomes. The prevalence of vitamin D insufficiency ranges from 9.3 to 41.4%, whereas that of vitamin D deficiency from 22.7 to 90.3%. A positive association with 25(OH)D concentrations exists for light skin color, white race, uncovered dressing pattern, maternal vitamin D supplementation and season of gestation (spring/summer). An inverse association exists for BMI and gestational age, whereas data for smoking and socioeconomic status are controversial. We concluded that vitamin D deficiency in pregnancy seems to be quite common, even in the Mediterranean region. Racial, social and cultural habits, as well as the absence of preventive supplementation/dietary strategies, seem to negate the benefits of sun exposure.

Vitamin D status during pregnancy: time for a more unified approach beyond borders?

Maternal hypovitaminosis D during pregnancy has been associated with a plethora of adverse health effects on the offspring. Maternal vitamin D status during pregnancy is affected by local climatic conditions. The aim of this article was to report on difficulties related to the heterogeneity of studies available in current literature on vitamin D status during pregnancy and discuss the incorporation of geophysical data in future studies, in an attempt to optimize their design and facilitate their interpretation. We focused on current vitamin D trials during pregnancy and their association with local regional climatic condition in geographical regions such as the Mediterranean basin based on our perspective on the field. Conduction of studies from areas with similar geophysical conditions is necessary, in order to extend our knowledge with respect to the question of which populations and under which circumstances would benefit most from vitamin D supplementation. Future vitamin D studies could benefit from the adoption of a unified concept minimizing these variations by selecting populations residing in areas with similar geophysical conditions adjusting also for their social and dietary habits.

Vitamin D and thyroid disease: to D or not to D?

The main role of vitamin D is to maintain calcium and phosphorus homeostasis, thus preserving bone health. Recent evidence has demonstrated that vitamin D may also have a role in a variety of nonskeletal disorders such as endocrine diseases and in particular type 1 diabetes, type 2 diabetes, adrenal diseases and polycystic ovary syndrome. Low levels of vitamin D have also been associated with thyroid disease, such as Hashimoto's thyroiditis. Similarly, patients with new-onset Graves' disease were found to have decreased 25-hydroxyvitamin D concentrations. Impaired vitamin D signaling has been reported to encourage thyroid tumorigenesis. This review will focus on the role of vitamin D in thyroid diseases, both autoimmune diseases and thyroid cancer, and will summarize the results of vitamin D supplementation studies performed in patients with thyroid disorders. Although observational studies support a beneficial role of vitamin D in the management of thyroid disease, randomized controlled trials are required to provide insight into the efficacy and safety of vitamin D as a therapeutic tool for this dysfunction.

Bone mineral density in men and children with haemophilia A and B: a systematic review and meta-analysis.

SUMMARY: Although haemophilia is not considered among the classic causes of secondary osteoporosis, the present meta-analysis provides strong evidence that men with haemophilia have a significant reduction in both lumbar spine and femoral bone mineral density, which appears to begin in childhood. INTRODUCTION: Haemophilia is not considered among the classic causes of secondary osteoporosis. The aim of this study was to systematically review the literature for case-control trials that have studied bone mass in males with haemophilia and to meta-analyze the best evidence available. METHODS: Electronic databases MEDLINE, EMBASE and CENTRAL were systematically searched for case-control trials that have studied bone mass in men or boys with haemophilia. Standardized mean difference (SMD) for bone mineral density (BMD) in the lumbar spine was the main study outcome and SMD in femoral neck and total hip BMD the secondary ones. Patient and control characteristics, such as age, body mass index (BMI), level of physical activity and blood-borne infections were recorded as possible predictors of the main outcome. RESULTS: Thirteen studies were included in the systematic review and ten in the main outcome meta-analysis. Men with haemophilia demonstrated reduced lumbar spine [random effects SMD [95 % confidence interval (CI)] = -0.56 (-0.84, -0.28), between-study heterogeneity (I (2)) = 51 %] and femoral neck BMD [random effects SMD (95 % CI) = -0.82 (-1.21, -0.44), I (2) = 63 %] compared with controls, which indicated a large and clinically significant association. Similar results were obtained for children [random effects SMD (95 % CI) = -0.92 (-1.77, -0.07), I (2) = 92 %]. No evidence of publication bias was detected. There was no evidence that age, BMI, level of physical activity or presence of blood-borne infections predicted lumbar spine BMD. CONCLUSIONS: This meta-analysis shows that men with haemophilia present a significant reduction in both lumbar spine and hip BMD, which appears to begin in childhood.