Endocrine Dysfunction in Cirrhosis: From Testosterone to Adrenal Precursors, Bridging Frailty and Prognosis

Endocrine alterations are a hallmark of chronic liver disease and are linked to malnutrition, sarcopenia and frailty [1-6]. However, data are limited regarding the independent impact of hormonal perturbations on survival [7]. Two prospective studies published in this issue of Liver International shed new light on the role of sex hormones and adrenal precursors in patients with decompensated cirrhosis. Sogbe et al. investigated 191 men undergoing evaluation for liver transplantation (LT). The authors focused on free testosterone (FT), the biologically active fraction of circulating testosterone. Patients with low FT had significantly higher MELD-Na scores, more frequent hepatic encephalopathy (HE) and worse liver frailty index (LFI) scores. Importantly, low FT—but not total testosterone (TT)—was associated with an increased risk of mortality (aSHR: 1.97; 95% CI: 1.07–3.61), adjusting for MELD-Na and frailty, and was associated with a lower probability of receiving LT. The second study by Adamantou et al. evaluated 124 men and postmenopausal women with decompensated cirrhosis, systematically assessing multiple hormonal axes, including the hypothalamic–pituitary–gonadal (HPG), hypothalamic–pituitary–adrenal (HPA) and growth hormone/IGF-1 pathways. Among all hormones evaluated, low dehydroepiandrosterone sulphate (DHEAS), an adrenal androgen precursor unaffected by the hepatic-derived sex hormone–binding globulin (SHBG) that binds to testosterone, was the only independent factor associated with abnormal physical performance and higher frailty by the liver frailty index (LFI) (aOR: 0.98; 95%: CI 0.97–0.99) and Short Physical Performance Battery (aOR: 1.11; 95% CI: 1.002–1.34), particularly in males. Low Δ4-androstenedione levels, an adrenal androgen precursor downstream of DHEAS—but not TT—were independently associated with increased mortality (HR: 0.64; 95% CI: 0.42–0.97). These studies converge on several key points. First, hormonal dysfunction is an independent prognostic factor in cirrhosis. Specifically, the HPG and HPA axes, including low FT, DHEAS and Δ4-androstenedione levels, are consistently linked with frailty and mortality beyond conventional liver disease scores. Second, TT is an unreliable marker in cirrhosis, reflecting the confounding effect of increased SHBG levels, which distort measurements and highlight the superiority of FT and adrenal precursors. Third, and perhaps of greatest novelty in the cirrhosis literature, frailty is a clinical phenotype of endocrine dysfunction. Both studies showed that lower androgenic activity, whether gonadal or adrenal, correlated with impaired muscle strength, worse physical performance and HE. These studies have begun to define the liver–endocrine axis, through which hepatic dysfunction disrupts the hormonal regulation of muscle metabolism, contributing to the development of the frailty phenotype. Mechanistically, testosterone suppresses myostatin, a myokine that promotes muscle breakdown, and stimulates IGF-1 signalling within the growth hormone/IGF-1 pathway, promoting muscle cell proliferation and muscle growth [8, 9]. Both studies established the importance of these endocrine pathways in muscle health and mortality in patients with cirrhosis (Figure 1). Mechanistic studies are required to clarify how adrenal precursors influence frailty and survival beyond their role as androgen reservoirs and to disentangle their interplay with myostatin, IGF-1 and systemic inflammation. These data must be interpreted in the context of their study design. First, there are challenges in generalisability. Sogbe et al. included only men awaiting LT. Both studies were small, and Adamantou et al. only included 39 postmenopausal women, limiting the power of sex-stratified analyses. Sex-specific differences should be systematically investigated, particularly in women, where menopause and adrenal androgen contributions may alter the prognostic weight of each hormone. Replication in larger and more diverse cohorts is needed, including stratified analyses by sex and aetiology, as the impact of metabolic syndrome and alcohol intake on hormonal pathways may differ from one another. The association between hormonal dysfunction, patient-reported outcomes and health-related quality of life is also needed. Second, FT was calculated indirectly by Sogbe rather than directly measured by equilibrium dialysis, which remains the gold standard [10]; in the latter study, multiple assays were used, raising concerns about reproducibility in clinical practice [11]. Third, both analyses were observational, and the impact of the therapeutic correction of hormonal deficiencies remains unknown. Fourth, as with all prognostic indices, validation and calibration are required before considering their use in bedside decision-making. The immediate implication for clinicians is awareness. Hormonal dysfunction is pervasive and clinically relevant in patients with cirrhosis [6, 7]. If indicated, testing FT or adrenal precursors should be considered and not TT. Identifying patients with low FT or DHEAS levels should prompt consideration of therapeutic replacement and could help flag individuals at higher risk of frailty and mortality [12]. Interventional trials are needed. Testosterone supplementation may improve muscle mass in men with cirrhosis [13-17]; however, safety concerns regarding hepatotoxicity, cardiovascular risk and oncogenesis persist [14]. It is also implicit but should be studied directly whether hormone replacement can improve one of the many domains of patient-reported outcomes likely impacted by deficiency [18]. These two studies expand the emerging field of hepatoendocrinology. While one study emphasises the prognostic importance of FT in men awaiting LT, the other extends the horizon by implicating adrenal androgens as key determinants of frailty and mortality in a broader population of patients with cirrhosis. The challenge ahead is to unravel the mechanistic pathways, test whether correcting hormonal deficiencies can modify the outcomes and assess the validity of integrating these endocrine biomarkers into risk stratification. Only then will we move from recognising hormonal dysfunction as a marker of poor prognosis to establishing it as a targetable pathway in the care of patients with advanced liver diseases. M.W. declare no conflicts of interest. Elliot B. Tapper has served as a consultant to Resolution, Novartis, Axcella, Iota, Satellite Bio, Korro Bio, Lipocine and Allergan; has served on advisory boards for Mallinckrodt, Bausch Health, Ipsen, Kaleido, Novo Nordisk; and has received unrestricted research grants from Gilead, Madrigal and Valeant. Jennifer C. Lai has served as a consultant for Novo Nordisk and Genfit; she has provided advisory services to Cosmo and Boehringer Ingelheim. Ezequiel Mauro received travel funding from Roche. This article is linked to https://doi.org/10.1111/liv.70384 and https://doi.org/10.1111/liv.70393.