The role of physical activity and exercise training in preventing the development of chronic disease and reducing mortality is increasingly recognized. A substantial body of evidence indicates that exercise confers these benefits to subsequent generations. This Review examines the effects of parental exercise, focusing on findings published within the past 10 years and related to mechanisms of transmission and sex-specific differences in both parents and offspring. Epigenetic modifications, including DNA methylation, histone modification and small non-coding RNAs, are crucial in how parental exercise influences offspring development. Paternal exercise alters the small RNA pool and methylation profiles in sperm, whereas maternal exercise affects both the in utero environment and postnatal lactation factors. Notably, male offspring show enhanced metabolic benefits, whereas female offspring exhibit greater cardiac improvements than male offspring. These findings highlight the sex-dependent nature of the generational effects of exercise and emphasize the need for further research into the molecular underpinnings and long-term implications for both male and female offspring.

Many diseases, including breast cancer, increase in women after menopause and with obesity. This Review addresses novel insights that link obesity, oestrogens, inflammation and breast cancer. Adipose tissue is chronically inflamed in obesity owing to pre-adipocyte expansion and activation of nuclear factor-κB (NF-κB), which upregulate pro-inflammatory cytokines. Obesity also impairs immunosurveillance. Emerging data indicate that the major oestrogens before and after menopause have opposing effects on inflammation. In contrast to the anti-inflammatory properties of premenopausal 17β-oestradiol, the dominant postmenopausal oestrogen, oestrone, is pro-inflammatory. Oestrone is synthesized in adipocytes, therefore the expanded adipose tissue biomass in obesity increases oestrone levels in both men and women, promoting NF-κB-driven inflammation. These pro-inflammatory effects of oestrone are also oncogenic, promoting breast cancer progression in laboratory models. The dominance of oestrone and loss of 17β-oestradiol might underlie the increased prevalence of hormone-responsive breast cancer after menopause, particularly in the context of obesity. Although oestrogens account for much of the excess breast cancer risk with obesity, data on 17β-oestradiol and oestrone levels in the breast and circulation in postmenopausal women, whether or not obesity is present, are limited. Weight loss is associated with reduced breast cancer risk and improved outcomes. The opportunity to use potent weight loss drugs as adjuncts to cancer therapy is discussed.

Deep concern has been raised about the reduced survival rate in patients with renal impairment, and efforts to identify comorbidities that could delay its progression are of paramount importance. Among them, thyroid dysfunction has been postulated as one of the determinants of chronic kidney disease (CKD). It is worth noting that the relationship between the thyroid gland and the kidney is mutual. Although patients with CKD can exhibit changes in thyroid function tests that characterize non-thyroidal illness syndrome, thyroid hormones per se are critical regulators of kidney structure and function. A growing number of studies indicate that subclinical hypothyroidism is more common in people with CKD than in the general population and could be considered a risk factor for the development of CKD. However, it remains unclear whether hypothyroidism has a causal role in the development of CKD or whether levothyroxine treatment could minimize the progressive loss of kidney function in these patients. Overall, this narrative Review intends to explore the potential involvement of thyroid dysfunction, with a focus on hypothyroidism, as a reversible risk condition in the deterioration of renal function.

Metabolic dysfunction-associated steatotic liver disease (MASLD; previously known as non-alcoholic fatty liver disease) is the leading cause of chronic liver disease worldwide and is closely linked to the obesity epidemic. MASLD often coexists with sarcopenia, an age-related loss of muscle mass and muscle function. These conditions are closely connected, and metabolic syndrome and its associated metabolic factors have a crucial role in their relationship. Metabolic syndrome considerably affects the risk and progression of MASLD and sarcopenia and promotes their development through various mechanisms. This Review explores the epidemiological link between MASLD and sarcopenia and the effect of metabolic syndrome and its components on both conditions, summarizing current treatment strategies and emerging evidence. To effectively manage both MASLD and sarcopenia, it is crucial to incorporate the five metabolic risk factors of metabolic syndrome into risk assessment and treatment strategies. Future research should continue to investigate the mechanisms linking metabolic syndrome, MASLD and sarcopenia. Establishing standardized definitions of sarcopenia for patients with MASLD and developing personalized treatment strategies through precision medicine will improve diagnosis, interventions and overall patient outcomes.

Hypothyroidism, which is characterized by reduced thyroid hormone production, affects approximately 5% of the general population. Although primarily associated with metabolic and endocrine alterations, hypothyroidism has also been associated with an increased risk for cardiovascular disease (CVD), mainly due to accelerated atherosclerosis. Although the association between overt hypothyroidism and CVD is well established, that between subclinical or mild hypothyroidism and CVD remains questionable. CVD is among the most common non-communicable diseases and is the leading cause of death globally. The present narrative Review delves into the intricate relationship between hypothyroidism and cardiovascular risk factors. It explores the biochemical and molecular mechanisms underlying the heightened susceptibility of the hypothyroid state to CVD, while also seeking to identify potential avenues for improving management and designing preventive strategies via examination of both conventional and new risk factors. Furthermore, the Review scrutinizes the reported role of thyroid hormones in modulating cardiac structure and function, to shed light on their influence on the development and progression of CVD. Risk evaluation and personalized treatment approaches for individuals with hypothyroidism are also discussed.

Hypophysitis is defined by inflammation of the pituitary gland and/or infundibulum. It can cause headaches and symptoms due to hypopituitarism. Diagnosis is based on a combination of hormonal and imaging parameters but can, in individuals with an uncertain diagnosis, require a transsphenoidal biopsy. While the risk of immune checkpoint inhibitor-induced hypophysitis is well known, several aetiologies of secondary hypophysitis have been identified and hypophysitis can also occur in relation to pregnancy. Primary hypophysitis is defined by the absence of a secondary cause of hypophysitis. Although each subtype can present with distinct clinical, endocrine and radiological features, extensive overlap makes the aetiological diagnosis difficult. Management of hypophysitis is another challenging task. Whereas some studies have suggested that high-dose glucocorticoids can improve pituitary function and alleviate symptoms, others have found limited benefit. Immunosuppressive agents have also been used as targeted therapy for the underlying condition or in individuals with aggressive hypophysitis, potentially improving both clinical presentation and hormonal function. These therapeutic approaches, used alone or in combination, can be considered in selected patients with primary, pregnancy-related or secondary hypophysitis. The aim of this comprehensive Review is to critically analyse the positive and aetiological diagnostic steps and the management of all subtypes of hypophysitis.

The intricate processes of feto-placental development are regulated by both genetics and the nutritional environment. The placenta mediates nutrient transfer to the fetus and waste transfer to the maternal circulation to facilitate proper fetal cell fate specification. Disruptions in these fate-regulatory programmes can lead to maternal and fetal complications. We explore how metabolic-epigenetic mechanisms programme feto-placental development, discussing the roles of metabolic sensing mechanisms. This Review covers the roles of nutrient metabolite-dependent protein modifications, lipid signalling, steroid signalling and oxygen signalling in regulating particular phases and lineages of feto-placental development. Understanding these environmental-genetic interactions is crucial for elucidating the limits of developmental plasticity, the pathogenesis of pregnancy-related disorders and the potential therapeutic windows we can leverage to improve maternal and fetal outcomes.

Work participation is beneficial for health. Diabetes mellitus is highly prevalent among adults, and although it poses a substantial healthcare cost burden, the true burden might be greater than is currently appreciated through effects on work participation. This Review summarizes the evidence regarding the effect of diabetes mellitus on paid employment. Several studies report increased risks of unemployment, early retirement and productivity loss among those with diabetes mellitus. The presence of diabetes mellitus complications and comorbidities probably further decreases work participation. Studies of workplace interventions demonstrate that work ability can be improved in people with diabetes mellitus. However, most existing research does not consider work characteristics (for example, type of work and working hours) in diabetes mellitus management. Whether diabetes mellitus itself increases occupational injury risk is unclear, with conflicting results reported. Most studies were cross-sectional and limited by use of self-reported diabetes mellitus and outcome measures, without consideration of the type of diabetes mellitus. Guidance on diabetes mellitus and employment has, to date, not been strongly grounded in evidence. Detailed research exploring factors implicated in work outcomes for people with diabetes mellitus, including age, sex, occupation and diabetes mellitus type, is needed to inform policy and support sustainable employment for those with diabetes mellitus.

Cystic fibrosis is a multisystem disorder caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and is characterized by progressive pulmonary decline and exocrine pancreatic insufficiency. People with cystic fibrosis are at risk of multiple endocrine complications that can substantially increase morbidity and mortality, including cystic fibrosis-related diabetes (CFRD) and cystic fibrosis-related bone disease (CFBD). Children and adolescents with cystic fibrosis can also experience compromised growth and delayed puberty, although advances in clinical care and treatment have reduced rates of these complications. However, as people with cystic fibrosis live longer and healthier lives, new health challenges associated with these endocrine complications will become increasingly prevalent, including microvascular and macrovascular disease, obesity, metabolic syndrome, osteoporosis, fractures and earlier onset of perimenopause. In this Review, we summarize current knowledge on the epidemiology, pathophysiology, diagnosis and treatment of CFRD, CFBD, growth and puberty, hypogonadism and infertility, iatrogenic adrenal insufficiency and perimenopause in patients with cystic fibrosis. We also consider future research priorities in the field.