Alcohol and the endocrine system: A critical review of disruptions, potential mechanisms, and health implications

Abstract

The endocrine system coordinates and integrates cellular activity throughout the body by regulating cellular and organ function and maintaining homeostasis. Homeostasis, the dynamic maintenance of internal balance despite changing external or internal conditions, is essential for proper cellular function. The endocrine system achieves this through a complex regulatory network of hormone‐mediated signaling among multiple endocrine organs, relying on precisely regulated synthesis and release of hormones and specific hormone‐receptor interactions. Endocrine‐mediated actions coordinate critical physiological processes, including growth, metabolism, reproduction, stress adaptation, and circadian rhythms throughout the lifespan. Endocrine glands—such as the hypothalamus, pituitary, thyroid, parathyroid glands, pancreas, adrenal glands, and gonads—secrete hormones that act via autocrine, paracrine, or endocrine mechanisms to influence target tissues. Hormonal actions are mediated by either cell surface receptors (e.g., G protein–coupled receptors for peptide hormones) or intracellular receptors (e.g., steroid and thyroid hormones). Hormone secretion is tightly regulated by feedback loops (e.g., cortisol inhibition of corticotropin releasing hormone [CRH] and adrenocorticotropin [ACTH] hormone) as well as by nutrient signals, neural inputs, and circadian cues. Alcohol, a commonly used substance, can impact the integrity of endocrine regulation of homeostasis at multiple sites and consequently contribute to risk for comorbid conditions. This review summarizes the physiological roles of key endocrine systems, delineates alcohol's effects as reported in both preclinical and clinical studies, discusses the clinical consequences and potential therapeutic implications of alcohol‐related endocrine dysfunction, and identifies areas in need of further research.

The endocrine system coordinates whole body cellular function and maintains homeostasis. Alcohol impacts the integrity of endocrine regulation at multiple sites, contributing to risk for comorbidities. Some of the alcohol‐mediated pathophysiological effects on the endocrine system include alterations in receptor expression and responsiveness, protein modifications leading to altered enzyme activity, altered neurotransmitter release and action, and epigenetic modifications. While the endocrine phenotype with acute or chronic alcohol is described, research identifying mechanisms of alcohol‐induced endocrine disruption is warranted.

INTRODUCTION

Alcohol‐induced alterations in endocrine function can result from either excess or deficiency in hormone production or action and may occur at multiple points along the hormone‐receptor signaling cascade. Endocrine glands—such as the hypothalamus, pituitary, thyroid, parathyroid glands, pancreas, adrenal glands, and gonads—secrete hormones that act via autocrine, paracrine, or endocrine mechanisms to maintain homeostasis.

Acute and chronic alcohol intake disrupts endocrine homeostasis through mechanisms that include direct cellular toxicity, dysregulation of neurotransmitter and hormone release, receptor desensitization or downregulation, epigenetic modifications, and oxidative or metabolic stress (Figure 1). Alcohol use disorder (AUD) is associated with widespread dysregulation across all major endocrine axes. Alcohol exposure across the lifespan, from gestation through advanced age, can disrupt numerous physiological processes, with effects that are often stage‐specific and influenced by existing comorbid conditions. Emerging evidence highlights increased alcohol use among vulnerable populations, including women and older adults, with implications for heightened risks of frailty, osteoporotic fractures, hormone‐sensitive cancers, and other endocrine‐related health outcomes.

FIGURE 1.

Summary of alcohol‐induced alterations in endocrine organ function. While for some systems, there seems to be a better understanding of how alcohol impacts hormone release or action, in many instances little is known about the underlying mechanisms explaining the alterations in endocrine function seen with acute and chronic alcohol use. Some of these are shared across tissues, and some of these may overlap with each other, synergizing to drive endocrine dysfunction. These include alterations in receptor expression and responsiveness, changes in enzyme expression and activity, alterations in oxidative capacity and mitochondrial health, impaired neurotransmitter release, decreases in dietary intake and absorption, and profibrotic changes.

While some studies report a J‐shaped curve where low to moderate alcohol use may be occasionally protective, consensus exists that heavy alcohol use increases all‐cause mortality (Lee et al., 2025). Moreover, alcohol use in the context of existing comorbidities has been increasingly recognized as a significant modifiable factor in health outcomes, particularly for metabolic comorbidities, compounding the impact of metabolic disease on all‐cause mortality (Tian et al., 2023) (Figure 2). Here, we review the impact of acute and chronic alcohol use on endocrine organ systems, integrating findings from preclinical and clinical studies. When available, identified mechanisms are discussed in context of the organ system affected.

FIGURE 2.

Principal functions of the endocrine system and potential sites of alcohol‐associated dysregulation. The endocrine system is critical in regulating processes from conception to aging, in acute scenarios as in the response to stress, maintaining energy balance, regulating minerals involved in blood pressure regulation, and in bone health. The figure on the right provides an overview of the potential comorbidities that patients with alcohol use disorder (AUD) may be at higher risk for because of alcohol's effect on the endocrine system. This raises the relevance of an integrated approach to the management of patients with AUD throughout their lifetime, particularly those that are already at risk for comorbid conditions.

HYPOTHALAMUS AND PITUITARY HORMONES

The hypothalamus, anatomically and functionally linked with the anterior and posterior pituitary, releases hormones through long axons terminating in the posterior pituitary and short axons terminating in the median eminence, from where peptides are transported to the anterior pituitary. The hormones released from the anterior and posterior pituitary regulate vital body functions maintaining homeostasis. The release of hypothalamic neuropeptides is regulated by afferent signals from other brain regions, from visceral afferents modulated by circulating levels of substrates and hormones and is exquisitely sensitive to the sleep/awake state of the individual. The critical role of the hypothalamus in regulating multiple organ systems can be affected by changes in light/dark, noise, fear, and anxiety. These signals are integrated by the hypothalamus and regulate hypothalamic neuropeptide release and control of pituitary function. Any of these mechanisms, as impacted by alcohol, can lead to alterations in hypothalamic function.

Alcohol drinking can disrupt sleep (Stein & Friedmann, 2005) and frequently coexists with anxiety (Anker & Kushner, 2019), two important modulators of hypothalamic hormone release. The photo‐neuroendocrine system consists of the pineal gland and the suprachiasmatic nucleus (SCN) of the hypothalamus and integrates environmental cues with intrinsic circadian oscillators. Cells in the pineal gland function as “neuroendocrine transducers” and secrete melatonin during the dark phase of the light/dark cycle in response to signals from retinal photoreceptors. Melatonin targets the SCN of the hypothalamus, a circadian oscillator. At the level of the hypothalamus, the central integrator of multiple endocrine systems, alcohol can alter neuropeptide release, reduce melatonin, and disrupt circadian rhythms. Alcohol has been reported to decrease melatonin release and to alter circadian rhythms resulting in what is known as asynchrony (Ekman et al., 1993; Grigsby et al., 2022; Nelson et al., 2024; Tran et al., 2025). Animal models show that neonatal alcohol exposure alters the circadian regulation of some molecular components of the clock mechanism in the rat SCN (Farnell et al., 2008). Moreover, chronic ethanol consumption and withdrawal markedly impair circadian clock photic phase‐resetting in mice (Brager et al., 2010). In humans, binge alcohol drinking disrupts hypothalamic circadian regulators and hormone release, especially in aging females. Individuals with an eveningness chronotype—those who naturally prefer later sleep and wake times—are particularly vulnerable to alcohol misuse, especially when experiencing social jet lag, the misalignment between their biological clock and socially imposed schedules (e.g., work or school obligations). This circadian misalignment has been associated with increased alcohol consumption, potentially due to disrupted sleep patterns, impaired impulse control, and heightened reward sensitivity during evening hours. The combination of eveningness chronotype and social jet lag constitutes a high‐risk phenotype for alcohol use, particularly among adolescents and young adults, and warrants further research to develop intervention strategies (Gulick & Gamsby, 2018; Samanta et al., 2024).

Two hormones are released from the posterior pituitary: antidiuretic hormone (ADH), also known as arginine vasopressin (AVP), and oxytocin. AVP is released in response to increased plasma osmolarity above a threshold of 280–284 mOsm and a greater than 10% decrease in blood volume. A rise in AVP release helps to restore fluid balance and arterial blood pressure by increasing water reabsorption and producing vasoconstriction. Alcohol decreases AVP release, and this is implicated in the disturbed water balance observed in actively drinking people with AUD and during acute withdrawal (Harper et al., 2018). The potential mechanisms implicated in decreased AVP release include a decrease in VP immunoreactive neurons, decreased synthesis of AVP, and accumulation of AVP peptide in neuronal nuclei.

Oxytocin is released from the posterior pituitary in response to sensory afferents triggered by the distention of the cervix toward the term of pregnancy and contraction of the uterus during parturition and in response to suckling of the nipple of the lactating breast. Acute alcohol has been reported to decrease oxytocin release, and this has been attributed to a decrease in the frequency of oxytocin spurts (Ryabinin & Fulenwider, 2021). The mechanisms responsible for decreased evoked oxytocin release may involve enhanced GABAergic transmission, reduced voltage‐gated Ca++ currents and increased large conductance of Ca++ activated K+ channel activation (Kumar et al., 2009; Walter & Messing, 1999). The inhibitory effects of alcohol on oxytocin can potentially impact the lactation process, as shown in clinical studies (Mennella et al., 2005). In addition to its endocrine effects, oxytocin plays a key role in several social, emotional, and affiliative behaviors across species (Bethlehem et al., 2014; Carter, 2014; Feldman, 2012). Oxytocin has been reported to contribute to the regulation of social bonding, maternal and parental behavior, stress regulation and anxiety, and social salience and attention. This has raised the possible link between oxytocin and motivation for alcohol drinking, highlighting the need for additional studies (King et al., 2021; Ryabinin & Fulenwider, 2021; Tunstall et al., 2019). Preclinical studies show support for oxytocin‐mediated decrease in conditioned place preference and alcohol self‐administration (Peters et al., 2013). Moreover, clinically, intranasal oxytocin significantly reduced alcohol withdrawal symptoms, including craving and anxiety scores (Pedersen et al., 2013). However, not all trials have shown consistent results and some have failed to show significant reduction in alcohol withdrawal scores as compared to placebo (Melby et al., 2019).

The anterior pituitary hormones belong to three families: growth hormone (GH) and prolactin, the proopiomelanocortin (POMC) derived, and the glycoproteins including thyroid‐stimulating hormone (TSH), luteinizing hormone (LH), and follicle‐stimulating hormone (FSH). The impact of alcohol on the glycoproteins released from the anterior pituitary is discussed in the context of the endocrine system where they are involved.

Growth hormone, synthesis and release from the anterior pituitary, is under positive regulation by growth hormone–releasing hormone (GHRH) and negative regulation by somatostatin (SS) and occurs in a pulsatile pattern, especially during slow‐wave sleep. GH stimulates insulin‐like growth factor 1 (IGF‐1) production, an important mediator of the anabolic and metabolic functions of GH. Alcohol produces significant alterations in the GH‐IGF‐1 pathway. Acute and chronic alcohol decrease nocturnal plasma levels of GH, reduce circulating GH and IGF‐1 levels, and attenuate the nightly peak of GH secretion (Dees et al., 2021; Ekman et al., 1996; Lands, 1999; Prinz et al., 1980). In addition, alcohol decreases tissue responsiveness to GH and IGF‐1, contributing to the alcohol‐mediated effects on anabolic responses (Frost & Lang, 2004). The underlying mechanisms of alcohol‐induced suppression of the GH‐IGF‐1 system include a decrease in hypothalamic GHRH expression, alterations in sleep pattern (decreased slow‐wave), and changes in secretagogue‐mediated release. Alcohol‐associated alterations in the GH‐IGF‐1 pathway can lead to growth impairment, reduced lean mass, delayed healing, and reduced bone density (Dees et al., 2021; Steiner & Lang, 2015).

Prolactin, secreted by the anterior pituitary, plays a key role in the development of mammary tissue and the initiation and maintenance of milk production. Its release is primarily regulated through negative control by hypothalamic dopamine (DA), which exerts tonic inhibition via D2 receptors on lactotroph cells. Suckling stimulates prolactin secretion by attenuating this dopaminergic inhibition. Multiple studies have shown that chronic alcohol consumption can lead to elevated circulating prolactin levels (hyperprolactinemia) in both men and women (Sarkar, 2010). Furthermore, alcohol has been reported to enhance estradiol‐induced proliferation of prolactin‐secreting cells and promote the development of prolactinomas. This effect may be mediated, at least in part, by alcohol‐induced downregulation of dopamine D2 receptor expression, thereby impairing DA's inhibitory control over prolactin secretion (De et al., 2002; Sarkar & Boyadjieva, 2007).

ADRENAL HORMONES

The adrenal glands produce and release steroid hormones cortisol, aldosterone, and androstenedione from the adrenal cortex and catecholamines from the adrenal medulla. The hypothalamic–pituitary–adrenal (HPA) axis regulates glucocorticoid (cortisol/corticosterone) secretion from the adrenal cortex and plays a critical role in coordinating the physiological response to stress. CRH released from the hypothalamus stimulates the synthesis of POMC and its subsequent posttranslational cleavage into adrenocorticotropic hormone (ACTH), β‐endorphins, and melanocyte‐stimulating hormone. ACTH stimulates the synthesis and release of glucocorticoids, which exert widespread effects on metabolism, immune function, and behavior and are essential for regulating the stress response and maintaining homeostasis under both basal and stress conditions.

Alcohol alters HPA axis function in a dose‐ and duration‐dependent manner, with distinct effects during acute use, chronic exposure, and withdrawal. Acute alcohol intake activates the HPA axis. In contrast, chronic alcohol use is associated with blunted HPA axis responsiveness, including reduced basal and stress‐induced CRH and ACTH release, flattened diurnal cortisol rhythms, and impaired glucocorticoid receptor sensitivity (Richardson et al., 2008). These neuroendocrine adaptations contribute to dysregulated stress responses, which are central to the pathophysiology of AUD, mood disorders, and relapse vulnerability.

During early abstinence or withdrawal, HPA axis activity often becomes dysregulated, with paradoxical increases in ACTH and cortisol levels reflecting impaired negative feedback mechanisms. These alterations in HPA function further reinforce anxiety, craving, and risk of relapsing, highlighting the complex and bidirectional relationship between AUD and stress‐related neuroendocrine signaling (Blaine & Sinha, 2017). Dysregulation of the HPA axis contributes to the compulsive nature of alcohol use, stress‐related relapses, and altered emotional regulation, and can impair immune function, promote visceral adiposity, and disrupt glucose metabolism, compounding alcohol‐related comorbidities.

Aldosterone, the principal mineralocorticoid produced by the adrenals, regulates renal potassium excretion and sodium reabsorption, contributing to long‐term blood pressure regulation. Alcohol has been reported to increase aldosterone levels (Aoun et al., 2018). Nonhuman primate and rodent studies show that plasma aldosterone rises significantly over time compared with baseline in response to chronic alcohol consumption. Alcohol‐dependent individuals who actively drink show higher plasma aldosterone levels compared with those who maintained abstinence. One controlled clinical study showed that acute ethanol ingestion stimulates components of the renin–angiotensin–aldosterone system (RAAS), resulting in increased renin and aldosterone levels (Husain et al., 2014; Puddey et al., 1985).

In addition to its central role in regulation of sodium and water balance, studies show a link between alcohol consumption behaviors and aldosterone (Aoun et al., 2018). Aldosterone levels positively correlated with both quantity of alcohol consumed, craving, and anxiety scores in animal models. Dependent rats showed reduced mineralocorticoid receptor (MR) gene expression in the central nucleus of the amygdala, which correlated with increased anxiety‐like behavior and compulsive alcohol drinking. This inverse association was also noted in nonhuman primates (Pince et al., 2023). A growing body of preclinical and early clinical research suggests that aldosterone and the MR may play a significant role in the development and maintenance of AUD. This has led to investigation of MR antagonists like spironolactone and eplerenone as potential pharmacological interventions for AUD (Farokhnia, Rentsch, et al., 2022). Observational retrospective studies show that spironolactone users reduced weekly alcohol use more than matched controls (Palzes et al., 2021). Ongoing clinical trials (spironolactone in alcohol use disorder [SAUD] ClinicalTrials.gov ID NCT05807139) test the safety and tolerability of spironolactone, co‐administered with alcohol, in individuals with AUD.

Androstenedione, the principal adrenal androgen, is a steroid hormone and key intermediate in the gonadal biosynthesis of both testosterone and estradiol. Alcohol can disrupt steroidogenesis at multiple levels, and its effect on androstenedione appears to be context‐, dose‐, and sex‐dependent, with potential implications for reproductive health, endocrine balance, and alcohol‐related comorbidities. Furthermore, the changes in circulating adrenal androgen levels may also be impacted by alcohol‐mediated changes in hepatic metabolism (Sarkola et al., 2000, 2001).

The adrenal medulla chromaffin cells (pheochromocytes) release catecholamines (epinephrine, norepinephrine, and dopamine) in response to sympathetic nervous system (SNS) stimulation. Acute and chronic alcohol use influences this system in a dose‐ and context‐specific manner. Acute alcohol activates the SNS, resulting in elevated plasma epinephrine and norepinephrine levels. This sympathetic surge contributes to tachycardia, elevated blood pressure, anxiety, and sweating seen during alcohol intoxication (Brunner et al., 2024). In contrast, chronic alcohol exposure may lead to downregulation of adrenergic receptors, impaired catecholamine reuptake and clearance, and baroreflex dysfunction (Brunner et al., 2021). Moreover, alcohol withdrawal can result in a rebound increase in sympathetic outflow, with significantly elevated plasma catecholamines contributing to tremors, hypertension, tachycardia, sweating, and anxiety (Ylikahri et al., 1980). These alcohol‐mediated effects highlight the increased risk for cardiovascular alterations during alcohol intoxication and withdrawal.

GONADAL HORMONES

The hypothalamic–pituitary–gonadal (HPG) axis regulates reproductive function via gonadotropin releasing hormone (GnRH), LH, FSH, and gonadal steroids (testosterone, estradiol). The female HPG axis regulates production of an ovum and ensures appropriate conditions for embryo implantation, fetal growth and development, and birth. The male HPG axis regulates spermatogenesis and male sexual development and behavior. Ovarian and placental hormones maintain pregnancy and prepare the breast for lactation. Estrogen, progesterone, and testosterone modulate GnRH release in a tightly regulated negative feedback loop. In addition to its effects on reproductive organs, estrogen has neuro‐ and cardio‐protective effects, protects against bone loss, and in the liver modulates the uptake of serum lipoproteins and the production of coagulation factors. Progesterone promotes follicle survival and oocyte maturation, facilitates implantation, and maintains pregnancy through stimulation of uterine growth and differentiation and suppression of myometrial contractility. In the brain, progesterone modulates sexual behavior and regulates body temperature.

Alcohol significantly influences the HPG axis in males and females, disrupting the regulation and balance of key reproductive hormones including testosterone, estradiol, progesterone, LH, and FSH. These effects are phase‐dependent, dose‐dependent, and influenced by age, use of hormonal contraception, and chronicity of alcohol use (Sarkola et al., 2000). Alcohol reduces GnRH secretion, impairs LH/FSH release (Ginsburg et al., 1996; Sarkola et al., 1999), disrupts steroidogenesis, and alters steroid hormone binding globulin (SHBG) levels (Bertello et al., 1983; Moosazadeh et al., 2024). Proposed mechanisms include an increase in aromatase activity, oxidative stress producing testicular damage, and decreased luteinizing hormone releasing hormone (LHRH) neuronal activity (Canteros et al., 1995; Gordon et al., 1979). In men, this causes hypogonadism and reduced sperm production, while in women, it causes menstrual irregularities, early menopause, and reduced fertility. Alcohol increases estrone, testosterone, and dehydroepiandrostenedione sulfate (DHEAS) in postmenopausal women, especially those on aromatase inhibitors, enhancing estrogen receptor positive breast cancer risk (Assi et al., 2020; Dorgan et al., 2001).

THYROID HORMONES

Thyroid hormone (TH) production is under regulation by the hypothalamic thyrotropin‐releasing hormone (TRH) stimulation of anterior pituitary release of TSH. TSH stimulates the thyroid gland synthesis and secretion of TH, tetraiodothyronine (T4) and triiodothyronine (T3) into circulation. TSH release is inhibited by glucocorticoids, somatostatin, and dopamine. TH plays a central role in modulation of energy metabolism, cardiovascular homeostasis, growth and development, and neurological function.

Numerous studies have described HPT axis dysfunction in people with AUD (Aoun et al., 2015; Balhara & Deb, 2013; Hermann et al., 2002; Ozsoy et al., 2006). Cross‐sectional clinical studies have reported reduced thyroid volume and serum T3 levels in subjects with AUD and cirrhosis (Hegedus, 1984). Moreover, reduced thyroid volume and increased thyroid fibrosis were reported from autopsies of individuals with AUD and cirrhosis as compared to matched controls (Hegedus et al., 1988 [Petrowski, 2025 #509]). Others have reported lower free T3 and T4 levels in late alcohol withdrawal, suggesting the involvement of stress hormones in modulation of TH homeostasis (Ozsoy et al., 2006). Alcohol decreases responsiveness of TSH to TRH and suppresses free T3 and T4. Decreased TSH response to TRH is also reported in depression and anorectic patients (Loosen, 1982), suggesting a biological link between AUD and comorbid conditions like depression. Rodent studies show blunted TSH response to cold exposure following a single acute injection of alcohol and an increase in TRH mRNA in PVN neurons following chronic (4 weeks) alcohol diet administration (Zoeller et al., 1996). Others have reported lower TSH following a 4‐week alcohol feeding period that was associated with increased liver type I deiodinase activity, indicating that changes in circulating TH levels associated with alcohol may result from a combination of central and peripheral effects (Nikodemova et al., 1998). Several mechanisms are proposed for alcohol‐induced alterations in thyroid function including a decrease in pituitary TRH receptors due to increased TRH release resulting from a decreased TSH responsiveness to TRH, a decrease in thyroid gland responsiveness to TSH, decreased thyroid volume, increased thyroid fibrosis, and alterations in deiodinase activity. These disruptions can occur with both acute and chronic alcohol use and may lead to clinical or subclinical hypothyroidism, especially in heavy drinkers (Hermann et al., 2002).

PARATHYROID HORMONE AND BONE METABOLISM

Parathyroid hormone (PTH), released from the parathyroid glands in response to decreased serum calcium levels, regulates calcium and phosphate homeostasis and contributes to regulation of bone health. PTH targets three main organs: the kidney, bone, and gut. PTH increases the activity of 1α‐hydroxylase in the kidney, the enzyme responsible for the last step involved in activating vitamin D, and increases the renal reabsorption of Ca2+ and excretion of inorganic phosphate (Pi). In bone, PTH stimulates bone turnover. In the intestines, PTH stimulates Ca2+ reabsorption. Alcohol acutely suppresses PTH, increases urinary calcium/magnesium loss, inhibits osteoblasts, and enhances osteoclast activity.

Ingestion of a single dose of alcohol was shown to produce a transient decrease in PTH and increase in serum phosphate and urinary calcium (Garcia‐Sanchez et al., 1995). Others have reported similar responses to acute alcohol intoxication in men and women, a transitory decrease in PTH followed by a rebound above baseline levels accompanied by an increase in urinary calcium excretion (Laitinen et al., 1991). Whether these changes are the result of decreased PTH synthesis, increased PTH degradation, or altered magnesium or calcium control of PTH release remains to be elucidated. The decline in the secretion of PTH accounts, at least in part, for the transient hypocalcemia, hypercalciuria, and hypermagnesuria that follow alcohol ingestion. Chronic alcohol use produces profound alterations, reflected by an inverse correlation between bone mineral density (BMD) and cumulative alcohol intake in heavy and moderate male alcohol drinkers without liver disease (Gonzalez‐Calvin et al., 1993). The deleterious impact of alcohol on bone homeostasis is likely to be aggravated in aging individuals, particularly in postmenopausal women, given the protective effects of estrogen on bone health, and this is less pronounced in young healthy individuals (Gonzalez‐Calvin et al., 1993). In vitro studies show that alcohol induced a dose‐dependent reduction in bone cell DNA and protein synthesis and a reduction in alkaline phosphatase activity (Friday & Howard, 1991). Confirmatory studies indicate that alcohol decreases osteoblast proliferation (Klein & Carlos, 1995), that may be linked to decreased polyamine metabolism. The effects on vitamin D appear to be inconsistent. Cross‐sectional studies of noncirrhotic male individuals with AUD with high calcium intake showed reduced levels of vitamin D compared with controls, but no significant decrease in BMD of lumbar and humeral areas (Laitinen et al., 1990). Preclinical studies show that rodents fed an alcohol diet for 10 months had decreased vitamin D, decreased trabecular bone, and increased bone medullary area suggestive of increased bone resorption (Turner et al., 1988). Studies in nonhuman primates show that chronic voluntary alcohol self‐administration for 10 months reduced intracortical bone porosity but did not alter tibia length, bone mass or density, mechanical properties, or mineralization (Kuah et al., 2024).

Implications of alterations in PTH and vitamin D homeostasis include increased risk of osteopenia, osteoporosis, fractures, and delayed healing, particularly in aging populations. Preclinical and clinical studies indicate that alcohol can impair bone formation, accelerate bone resorption, alter gonadal hormones, and affect nutritional status of the individual. Persons with AUD show increased total, osteoporotic, and hip fracture risk compared with nondrinkers (Godos et al., 2022; Ke et al., 2023), and this may depend on pattern of alcohol use and bone site (Wang et al., 2020), and a combination of endocrine, nutritional, lifestyle, and alcohol drinking patterns (Turner et al., 2021). An additional consideration, particularly in the aging population, is the increased risk for falls associated with loss of balance and muscle strength, which further complicates musculoskeletal health, increases fracture risk, and decreases the bone fracture healing process (Eby et al., 2022).

PANCREATIC HORMONES AND GLUCOSE HOMEOSTASIS

While effects of alcohol on exocrine pancreatic function have established increased risk for pancreatitis through metabolic toxicity, alterations in intracellular Ca++, enzyme activation, fibrosis, inflammation, and ER stress, less is known on the mechanism underlying pancreatic endocrine function (Clemens et al., 2014). The endocrine pancreas produces and releases insulin and glucagon, both of which play critical roles in maintaining glucose homeostasis. Insulin stimulates glucose uptake, fatty acid transport, and protein synthesis. Glucagon opposes insulin's effects in the liver, promoting hepatic glucose output.

Clinical studies show that alcohol decreases circulating basal insulin levels (Bonnet et al., 2012) and the insulin and c‐peptide responses to glucose (Patto et al., 1993). Chronic alcohol feeding in preclinical models decreased the ability of ß‐cells to release insulin and this was associated with decreased glucokinase, Glut2, ATP, and insulin expression, suggesting that the glucose‐sensing machinery of the ß‐cell is compromised by alcohol (Kim et al., 2010). Moreover, those studies showed tyrosine nitration of glucokinase, preventing its association with downstream signaling molecules, potentially contributing to impaired insulin release. In vitro studies confirm alcohol‐induced reduced insulin secretion and identify additional pathways, namely interfering with muscarinic signaling and protein kinase C (PKC) activation but not the K‐ATP channels. These effects were prevented by inhibition of alcohol metabolism, suggesting that alcohol metabolism contributes to the suppression of insulin release. In contrast, others have reported an acute alcohol‐induced blood flow redistribution (Nguyen, Lee, & Nyomba, 2012) favoring the endocrine pancreas that augmented a late‐phase insulin secretion following a glucose load in rodents (Huang & Sjoholm, 2008).

The effects of alcohol on regulation of insulin and glucose metabolism may be influenced by several factors including the nutritional status, acute or chronic response to alcohol and patterns of alcohol use (Steiner et al., 2015). Studies on the effects of alcohol use and development of insulin resistance are inconsistent. Moderate alcohol consumption is negatively associated with insulin resistance (Beulens et al., 2008; Bonnet et al., 2012; Greenfield et al., 2003; Hulthe & Fagerberg, 2005; Magis et al., 2003; Schrieks et al., 2015), while many human (Andersen et al., 1983; Shelmet et al., 1988; Yki‐Jarvinen & Nikkila, 1985) and rodent (Dziadulewicz et al., 2007; He et al., 2006; Kim et al., 2014; Lang et al., 2014; Nguyen, Le, et al., 2012; Rasineni et al., 2019; Wan et al., 2005; Xu et al., 1998; Zhao et al., 2009) studies report increased metabolic dysregulation and insulin resistance with unhealthy alcohol use. In contrast, others have reported enhanced insulin action and no alteration in ß‐cell insulin secretion following an acute alcohol drink in a small (N = 8) number of individuals (Avogaro et al., 2004), while others have reported decreased insulin and glucagon secretion following acute intragastric or intravenous alcohol administration in healthy men (Lanng et al., 2019).

Despite the occasional reports of inconsistent effects of alcohol on pancreatic endocrine function, the overwhelming majority of preclinical and clinical studies show that chronic alcohol increases metabolic dysregulation, impairs pancreatic response to a glucose load and decreases glucose utilization (Cao et al., 2024; Ford Jr. et al., 2016; Yoo et al., 2016). These observations strongly suggest that chronic heavy alcohol use may contribute to insulin resistance, impaired glucose tolerance, and type 2 diabetes, increasing the risk of cardiovascular disease and cognitive decline. This is relevant to the currently growing burden of metabolic disease and its contribution to reduced quality of life, increased healthcare utilization, and significant economic strain. Metabolic diseases including obesity, type 2 diabetes mellitus (T2DM), metabolic syndrome, and dyslipidemia are leading contributors to global morbidity and mortality through their contribution to cardiovascular disease, cancer, chronic kidney disease, and other noncommunicable diseases (NCDs). The Global Burden of Disease (GBD) study highlights that globally, high fasting plasma glucose, high body mass index (BMI), and dyslipidemia are among the top modifiable risk factors contributing to years of life lost (YLL) and years lived with disability (YLD) (1). T2DM is associated with a 1.5‐ to 2‐fold increased risk of all‐cause mortality, with cardiovascular disease accounting for most deaths (Rawshani et al., 2017). Poor glycemic control and presence of comorbidities (e.g., hypertension, nephropathy) further amplify this risk (Mottillo et al., 2010). Interestingly, light‐to‐moderate alcohol consumption in healthy women was reported to be associated with enhanced insulin sensitivity, reduced basal insulin secretion rate and lower fasting plasma glucagon concentration, suggesting a reduced risk of diabetes (Bonnet et al., 2012). Overall, the impact of alcohol on multiple aspects of metabolic homeostasis appears to be dependent on whether alcohol ingestion is acute or chronic, the nutritional and fed state of the individual, and the existence of comorbid conditions including diabetes and obesity. This complex interaction of alcohol with metabolic regulation calls for more research given the prevalence of alcohol use and the growing incidence of obesity and metabolic syndrome in modern cultures.

IMPACT OF ALCOHOL ON NONCANONICAL ENDOCRINE TISSUES

More recently, we have come to appreciate the endocrine function of nontraditional endocrine tissues. Adipose tissue, skeletal muscle, and the gastrointestinal tract have been shown to release hormones and mediators into the systemic circulation, and these exert endocrine‐like actions in distant organs. And many of these are significantly impacted by alcohol. Adipokines are bioactive peptides secreted by adipose tissue that regulate energy balance, glucose metabolism, inflammation, and neuroendocrine function. Emerging evidence indicates that alcohol consumption modulates adipokine expression and circulating levels in a dose‐, duration‐, and context‐dependent manner, with important implications for metabolic regulation, systemic inflammation, and alcohol‐related organ injury.

Adiponectin, an antiinflammatory and insulin‐sensitizing adipokine, is influenced by both acute and chronic alcohol exposure. Short‐term moderate alcohol consumption (~30–40 g/day) has been shown to increase circulating adiponectin levels in healthy individuals, potentially modulating insulin sensitivity (Sierksma et al., 2001). In contrast, chronic heavy alcohol use, particularly in rodent models of alcoholic liver disease, is associated with suppressed adiponectin production, possibly due to oxidative stress and adipose tissue dysfunction (Kasztelan‐Szczerbinska et al., 2013).

Leptin, an adipokine involved in satiety signaling and energy expenditure, is acutely suppressed by alcohol intake, with reductions observed in both daytime and nighttime levels (Rojdmark et al., 2001). However, in individuals with AUD, leptin levels are often elevated and positively associated with pro‐inflammatory cytokines, such as TNF‐α, as well as with alcohol craving and relapse risk (Kiefer et al., 2005). Notably, leptin levels may remain unchanged in early abstinence, with some sex‐ and time‐dependent variability reported (Addolorato et al., 2009; Hillemacher et al., 2007).

Ghrelin, a gut‐derived orexigenic hormone that modulates reward pathways, is increased by moderate alcohol intake (Sierksma et al., 2001). In individuals with AUD, ghrelin levels are dysregulated and tend to rise during early withdrawal, although findings regarding its relationship to craving and relapse have been inconsistent (Addolorato et al., 2006).

Resistin, an adipokine linked to insulin resistance and inflammation, appears to be less sensitive to acute alcohol intake in healthy individuals (Sierksma et al., 2001). However, elevated resistin levels have been observed in patients with alcoholic cirrhosis, where they correlate with markers of systemic inflammation and liver disease severity (Kasztelan‐Szczerbinska et al., 2013).

Overall, alcohol‐induced alterations in adipokine signaling contribute to a pro‐inflammatory and metabolically dysregulated state, particularly in chronic alcohol use and liver disease. These changes may influence not only peripheral metabolic outcomes but also central pathways related to reward, stress reactivity, and addiction, positioning adipokines as potential biomarkers and therapeutic targets in alcohol‐related disorders.

Glucagon‐like peptide‐1 (GLP‐1) is a gut‐derived incretin hormone with key roles in glucose metabolism, appetite regulation, and body weight control. GLP‐1, released by enteroendocrine L cells in the small intestine and colon, enhances glucose‐stimulated insulin secretion (glucose‐dependent), suppresses glucagon secretion, slows gastric emptying, reducing postprandial glucose spikes, reduces appetite and food intake, and promotes satiety. Originally studied for its incretin effects, GLP‐1 has emerged as a multifunctional hormone with additional effects including modulation of alcohol drinking and associated behaviors.

Data from preclinical studies show that microinjection of GLP‐1 receptor agonists (RA) into the ventral tegmental area and nucleus accumbens reduces alcohol intake and seeking behaviors in rodents (Chuong et al., 2023). Others have demonstrated that systemic administration of GLP‐1RA crosses the blood‐brain barrier and attenuates alcohol drinking, alcohol‐induced locomotion, and nucleus accumbens dopamine release, supporting central mechanisms in GLP‐1RA mediated suppression of alcohol drinking and related behaviors (Aranas et al., 2023). Clinical data have also provided evidence of an alcohol‐GLP‐1 interaction that may modulate alcohol drinking. Oral and intravenous alcohol administration to people with AUD enrolled in human laboratory experiments was reported to result in significant reduction of GLP‐1 levels. In addition, postmortem samples showed that GLP‐1R gene expression levels in the hippocampus correlated with behavioral measures of alcohol drinking, highlighting a possible link between alcohol drinking and the GLP‐1 system (Farokhnia, Browning, et al., 2022). Others reported decreased GLP‐1 in women following consumption of an acute dose of alcohol (Molina‐Castro et al., 2024). Subsequently, a clinical trial (ClinicalTrials.gov: NCT03232112) examined the impact of the GLP‐1 agonist exenatide on the number of heavy drinking days in AUD patients. Results showed that exenatide did not significantly reduce the number of heavy drinking days compared with placebo but significantly attenuated functional magnetic resonance imaging alcohol cue‐reactivity in the ventral striatum and septal area, which are crucial brain areas for drug reward and addiction. Subsequent studies have provided evidence supporting the use of GLP‐1R agonists (e.g., semaglutide) for reducing alcohol intake and improving metabolic function (ClinicalTrials.gov NCT05520775) (Farokhnia et al., 2025; Hendershot et al., 2025; Jerlhag, 2025). Ongoing clinical trials show decreased alcohol craving and decreased alcohol consumption in response to GLP‐1R agonist administration. Observational data show that GLP‐1R agonist use lowers AUD relapses and decreases risk of hospitalization due to AUD. However, additional studies are warranted to provide definitive evidence of a beneficial effect of GLP‐1R agonists in AUD (Lahteenvuo et al., 2025; Subhani et al., 2024). No studies have focused on the mechanisms mediating alcohol‐induced suppression of GLP‐1 release. However, alcohol‐mediated alterations in neurotransmission could be involved. Muscarinic (M1) receptor signaling has been reported to be involved in GLP‐1 release in the gut in response to nutrients (Anini et al., 2002). It is possible that the presence of luminal alcohol could interfere with nutrient signaling resulting in GLP‐1 release. Alternatively, it is also possible that alcohol modulation of vagal pathways within the enteric nervous system, similar to that reported in the cardiovascular system (Reed et al., 1999), could also contribute to impaired GLP‐1 release (Rocca & Brubaker, 1999).

CONCLUSION

In summary, we provided a brief overview of the endocrine system and highlighted some of the alterations produced by alcohol intake or administration. Alcohol's pervasive effects on the endocrine system disrupt multiple axes, contributing to a spectrum of clinical disorders (Figure 2). While for some systems, there seems to be a better understanding of the mechanisms involved in alcohol‐mediated effects on hormone release or action, in many instances little is known about the underlying mechanisms explaining the alterations in endocrine function seen with acute and chronic alcohol use. It is likely that some of the underlying mechanisms are shared across tissues and may overlap with each other synergizing to drive alcohol‐induced endocrine dysfunction. Moreover, it is possible that some of the peripheral effects of alcohol on endocrine organs may in turn impact behaviors including craving, alcohol seeking, and reward.

Several mechanisms and pathways have been identified as mediators of alcohol‐mediated tissue injury, including inflammation, oxidative stress, and profibrotic remodeling in some organs. While these have been identified as relevant in some endocrine organs (i.e., inflammation and fibrosis in the pancreas; oxidative stress in testes) others emerge as relevant and pertinent to endocrine alterations. These include alterations in receptor expression and responsiveness, protein modifications leading to altered enzyme activity, altered neurotransmitter release and action, and epigenetic modifications. Moreover, alcohol metabolism appears to contribute to impairments in endocrine function as well, as in the case of ß‐cell impairment of insulin release. It is important to emphasize this is by no means a complete list and reflects to a large extend the dearth in research focused on identifying mechanisms of alcohol‐induced endocrine disruption in favor of studies describing the endocrine phenotype resulting from acute and chronic alcohol consumption, highlighting that much research remains to be done.

An important area also in need of further research is in the investigation of alcohol‐induced endocrine dysfunction across the lifespan as it impacts vulnerable stages of development, from in utero exposure to the increasingly frequent use of alcohol in aging populations. Similarly, the sex differences in vulnerability to alcohol‐associated endocrine effects is of importance and remains under explored.

A comprehensive understanding of alcohol‐associated endocrine disruptions is essential for early diagnosis, risk stratification, and treatment planning. Integrating endocrine evaluation into AUD management may enhance outcomes, particularly as dual‐purpose therapeutics like GLP‐1R agonists emerge. Continued research into endocrine–behavioral feedback, sex differences, and transgenerational impact will be critical for advancing personalized care in alcohol‐related disorders.

FUNDING INFORMATION

This work was supported by grants from the NIH/NIAAA: P60AA009803 to PEM.

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.

Molina, P.E. & Simon, L. (2026) Alcohol and the endocrine system: A critical review of disruptions, potential mechanisms, and health implications. Alcohol: Clinical and Experimental Research, 50, 1–13. Available from: 10.1111/acer.70221

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.