ALCOHOL RESEARCH: Current Reviews

Pathophysiology of the Effects of Alcohol Abuse on the

Nadia Rachdaoui, Ph.D., and Dipak K. Sarkar, Ph.D., D.Phil. Nadia Rachdaoui, Ph.D., is an assistant research professor, and Alcohol can permeate virtually every organ and tissue in the body, resulting in tissue Dipak K. Sarkar, Ph.D., D.Phil., is injury and organ dysfunction. Considerable evidence indicates that alcohol abuse Board of Governors Distinguished results in clinical abnormalities of one of the body’s most important systems, the endocrine system. This system ensures proper communication between various Professor, in the Rutgers Endocrine organs, also interfacing with the immune and nervous systems, and is essential for Research Program, Department maintaining a constant internal environment. The endocrine system includes the of Animal Sciences, Rutgers hypothalamic–pituitary–adrenal axis, the hypothalamic–pituitary–gonadal axis, the University, New Brunswick, hypothalamic–pituitary– axis, the hypothalamic–pituitary–growth / New Jersey. -like growth factor-1 axis, and the hypothalamic– axis, as well as other sources of , such as the endocrine and endocrine . Alcohol abuse disrupts all of these systems and causes hormonal disturbances that may result in various disorders, such as stress intolerance, reproductive dysfunction, thyroid problems, immune abnormalities, and psychological and behavioral disorders. Studies in both humans and animal models have helped shed light on alcohol’s effects on various components of the endocrine system and their consequences.

Key words: Alcohol consumption; alcohol use, abuse, and dependence; harmful effects of alcohol; pathophysiology; endocrine system; ; pituitary gland; hormones; hormonal disturbances; endocrine pancreas; endocrine adipose tissue; immune system; humans; animal models

Alcohol abuse can result in clinical the body is affected by the endocrine dysfunction, certain cancers, bone dis- abnormalities of one of the body’s system. Its hormones control metabolism ease, and psychological and behavioral most important systems, the endocrine and energy levels, electrolyte balance, disorders. Alcohol use has been shown system. Together with the nervous sys- growth and development, and repro- to affect many hormone systems, tem, the endocrine system is essential duction. The endocrine system also is including the hypothalamic–pituitary– for controlling the flow of information essential in enabling the body to respond adrenal (HPA) axis, the hypothalamic– between the different organs and cells to, and appropriately cope with, changes pituitary–gonadal (HPG) axis, the of the body. The nervous system is in the internal or external environ- hypothalamic–pituitary–thyroid (HPT) responsible for rapid transmission of ments (e.g., changes in the body’s axis, the hypothalamic–pituitary– information between different body temperature or in the electrolyte /insulin-like growth regions, whereas the endocrine system, composition of the body’s fluids) as factor-1 (GH/IGF-1) axis, and the which is composed of a complex sys- well as to respond to stress and injury. hypothalamic–posterior pituitary tem of glands that produce and secrete Both acute and chronic exposure to (HPP) axis. After a brief overview of hormones directly into the blood cir- alcohol may have differential direct the hormones of the hypothalamus culation, has longer-lasting actions. and indirect effects on endocrine func- and pituitary gland, this article dis- Together, the nervous system and the tions. Alcohol intoxication induces cusses the adverse effects of both acute endocrine system ensure proper com- hormonal disturbances that can disrupt and chronic alcohol exposure on the munication between various organs of the body’s ability to maintain homeo- different components of these hor- the body to maintain a constant inter- stasis and eventually can result in vari- mone systems based on recent findings nal environment, also called homeo- ous disorders, such as cardiovascular from human and animal studies. In stasis. Almost every organ and cell in diseases, reproductive deficits, immune addition, alcohol influences the release

Pathophysiology of the Effects of Alcohol Abuse on the Endocrine System | e-1 and actions of the pituitary hormone and tissues (e.g., breast, muscle, , other homeostatic challenges, neurons (outlined in the sidebar bone, and skin) (see the table). in the PVN of the hypothalamus syn- “Alcohol and Prolactin”) as well as of The posterior or neurohypophyseal thesize and secrete CRF and AVP. At hormones produced and released in lobe of the pituitary contains the the , CRF binds to other tissues, such as the endocrine terminals of certain neurons (i.e., mag- CRF1 receptors and stimulates specific pancreas and the adipose tissue (reviewed nocellular - and - cells (i.e., corticotropic cells) to synthe- in the sidebar “Alcohol and Other producing neurons) originating in two size and secrete a peptide called proop- Endocrine Tissues”). specific sections (i.e., the paraventricu- iomelanocortin (POMC). POMC can lar nuclei [PVN] and supraoptic nuclei) be cleaved into several smaller peptides, of the hypothalamus. These neurons including ACTH; β-endorphin (BEP); Hormones of the Hypothalamus secrete primarily two hormones from and three similar peptides called α-, and Pituitary Gland the posterior pituitary into the systemic β-, and γ-melanocyte stimulating hor- blood: arginine vasopressin (AVP), mones. The POMC in the anterior The hypothalamic–pituitary axis can which controls the renal water han- pituitary primarily is processed into be considered the coordinating center dling and cardiovascular functions, ACTH, whereas BEP mainly is derived of the endocrine system. The hypo- and oxytocin, which regulates milk from POMC produced in the hypo- thalamus is the main neural control ejection during lactation and uterine thalamus (i.e., the ventromedial arcu- center, also known as the “master contractions during birth. Evidence ate nucleus). At the same time, the switchboard,” which coordinates also indicates that both AVP and AVP binds to V1b receptors, potenti- nervous and endocrine system func- oxytocin act not only as hormones ating the effects of CRF on ACTH tions. The hypothalamus consolidates but also as neuromodulators and production in the anterior pituitary. inputs derived from higher brain cen- neurotransmitters within the central ACTH then is released into the sys- ters, various environmental cues, and nervous system (de Wied et al. 1993; temic circulation, where it binds to endocrine feedback. Neurons within Stoop 2014). However, AVP and specific receptors (i.e., melanocortin the hypothalamus produce and secrete oxytocin also can be produced in type 2 receptors) on cells in an area releasing hormones, such as corticotro- another group of neurons in the PVN called the zona fasciculata in the outer pin-releasing factor (CRF), luteinizing and supraoptic nuclei (i.e., in the par- layer (i.e., cortex) of the adrenal glands hormone–releasing hormone (LHRH), vocellular neurons) and released into that are located on top of the kidneys. thyrotropin-releasing hormone (TRH), the hypothalamic–hypophyseal portal There, ACTH stimulates the production and growth hormone–releasing hor- vessels to reach the anterior pituitary. of hormones—mainly mone (GRH), as well as inhibiting There, AVP acts synergistically with in humans and corticosterone hormones, such as and CRF to promote secretion of ACTH in rodents. These hormones then initi- , directly into the blood vessel (Plotsky 1991). In contrast, oxytocin ate a cascade of biological responses connecting the hypothalamus with the acts on specialized cells in the anterior that help counteract the altered homeo- pituitary gland (i.e., the hypothalamic– pituitary to promote prolactin secre- static state. achieve hypophyseal portal vein). These hor- tion (Sarkar and Gibbs 1984). their effects by binding to widely dis- mones then control the synthesis and tributed high-affinity mineralocorticoid release of hormones in the pituitary receptors and low-affinity glucocorticoid gland. The pituitary gland comprises Alcohol and the HPA Axis receptors on their target cells. These two sections—the adenohypophysis, receptors then translocate to the cell or anterior lobe, and the neurohypoph- nucleus, where they bind to specific ysis, or posterior lobe. In response to Normal Functioning of the HPA Axis DNA sequences called glucocorticoid signals from the hypothalamus, the response elements of genes that are anterior pituitary produces and secretes The HPA axis (figure 1) is one of the responsive to glucocorticoids, thereby trophic hormones, which are hormones endocrine pathways most sensitive to positively or negatively regulating the that have a growth effect on the organs the effects of alcohol abuse. This hor- expression of those genes. or tissues they are targeting. They include, mone system controls the stress-response The activity of the HPA axis is regu- among others, adrenocorticotropic pathways and regulates many of the lated through several feedback mecha- hormone (ACTH), thyroid-stimulating body’s physiological processes, such nisms. The principal protection against hormone (TSH), follicle-stimulating as metabolic, cardiovascular, and overactivation of the HPA axis involves hormone (FSH), immune functions. It integrates physi- the glucocorticoids (e.g., cortisol) (LH), prolactin, and growth hormone cal and psychosocial stimuli to allow through a negative feedback loop. (GH) and modulate the functions of the body to maintain homeostasis. In Thus, glucocorticoids bind to miner- several peripheral endocrine glands response to stress (i.e., psychological, alocorticoid (type 1) receptors and (i.e., adrenal glands, thyroid, and ) physical, or infectious stressors) or glucocorticoid (type 2) receptors in e-2 | Vol. 38, No. 2 Alcohol Research: Current Reviews Alcohol and Prolactin

Prolactin, also known as luteotropin, an average daily alcohol intake of communication between lactotropic is a polypeptide hormone produced 170 g (i.e., approximately 12 standard and other pituitary cells (De et al. 2002). and secreted by specialized cells in drinks) for 2 to 16 years (Valimaki The inhibitory action of hypotha- the anterior pituitary called lactotro- et al. 1984). Elevated prolactin levels lamic dopamine on pituitary prolactin pes. As the name indicates, prolactin also were reported in women with secretion is mediated by the dopamine is involved in the maintenance of AUD and admitted for alcoholism G-protein–coupled D2 receptors lactation by the mammary glands. treatment who reported drinking (D2R), which interact with regula- However, prolactin also has been an average of 84 g of alcohol (i.e., tory molecules called G-proteins and implicated in a plethora of other approximately 7 standard drinks) specifically a subtype called adeny- biological functions or responses, per day for at least 7 years (Seki et lyl-cyclase–inhibitory Gi/Go (Ben- such as mammary-gland development; al. 1991). Alcohol-induced hyper- Jonathan et al. 2001; Sarkar 2010). reproduction; immune functions; prolactinemia also was evident in There are two isoforms of the D2R, and behavioral functions, including postmenopausal women (Gavaler a long (D2L) and a short (D2S) learning, memory, and adaptation. 1994) and in men with AUD isoform.1 Chronic exposure to ethanol Prolactin is regulated by numerous (Soyka et al. 1991). increases the expression of prolactin mechanisms, including both inhibi- Studies in nonhuman primates mRNA and of D2L mRNA but tory and stimulatory signals from and laboratory animals have con- decreases expression of D2S both in the hypothalamus. The main hypo- firmed an alcohol-induced hyper- the pituitary of Fischer-344 rats and thalamic factor responsible for prolactinemia. For example, acute in primary cultures of anterior pitu- inhibition of prolactin release is ethanol administration increased itary cells (Oomizu et al. 2003). In dopamine. Thus, prolactin secretion serum prolactin levels in male addition, exposure of ovariectomized is controlled by a short-loop inhibi- (Seilicovich et al. 1985) and female rats to ethanol for 2 to 4 weeks tory feedback effect, whereby elevated (Dees and Kozlowski 1984) rats. reduced the expression of two other prolactin levels in the circulation Similarly, chronic self-administration G-proteins, Gi2 and Gi3 (Chaturvedi stimulate the hypothalamus to release of alcohol (3.4 g/kg/day) in female and Sarkar 2008). Similar results dopamine, which then acts on the monkeys was associated with an were found in experiments using pituitary to stop further prolactin increase in plasma prolactin levels various cell culture models (Sengupta release. Dopamine also can block and Sarkar 2012). prolactin release directly at the level (Mello et al. 1988) as well as appar- Finally, ethanol treatment had of lactotropes. In addition to dopa- ent enlargement (i.e., hyperplasia) differential effects on various mine, γ-aminobutyric acid released of the pituitary as demonstrated by G-proteins in cells expressing only by hypothalamic neurons inhibits immunocytochemical examination prolactin release. Conversely, several (Mello et al. 1983). Ethanol also D2S or D2L, eliciting a marked hypothalamic factors stimulate increased plasma prolactin levels and increase in Gs expression and a prolactin release from the anterior pituitary weight both in female rats decrease in Gi3 expression in D2S pituitary, including thyrotropin- with normal menstrual cycles and in cells but a moderate increase in Gs releasing hormone, vasoactive intes- rats whose had been removed and marked increase in Gi3 expres- tinal peptide, oxytocin, β-endorphin, (i.e., ovariectomized rats) and pro- sion in D2L (Sengupta and Sarkar , substance P, serotonin, moted -induced develop- 2012). Taken together these studies and . ment of prolactin-producing benign indicate that ethanol diminishes Several reports have indicated that tumors (i.e., prolactinomas) in the dopamine’s ability to inhibit prolac- chronic alcohol use can cause excessive pituitary (De et al. 1995). Finally, tin secretion by altering the process- levels of prolactin in the blood (i.e., ethanol increased basal and estradiol- ing (i.e., splicing) of D2R mRNA, hyperprolactinemia) in both men mediated proliferation of lactotropic promoting the increase of the D2L and women. For example, persistent cells in primary cultures of mixed isoform, as well as by differentially hyperprolactinemia was observed anterior pituitary cells, but failed to altering the expression of various Gi in women with alcohol use disorder do so in cultures of only lactotropic and Gs proteins in lactotropic cells. (AUD) and no clinical evidence of cells, indicating that ethanol’s effects 1 The D2S isoform results from an exclusion of the sixth exon alcoholic liver cirrhosis who reported on proliferation require cell-to-cell of the D2R gene in the mature transcript.

Pathophysiology of the Effects of Alcohol Abuse on the Endocrine System | e-3 Alcohol and Prolactin (continued)

Ethanol exposure affects prolactin such as TGFβ-3 and basic fibroblast epigenetic mechanisms. PLoS One 10(10):e0140699, production not only in adults but growth factor, in the pituitary gland; 2015. PMID: 26509893 also in the developing fetus. Fetal similar results were found in isolated Gavaler, J.S. Aging and alcohol: The hormonal status of postmenopausal women. In: Sarkar, D.K., and Barnes, alcohol exposure from day 7 to day cell cultures enriched for lactotropes C., Eds. Reproductive Neuroendocrinology of Aging 21 of gestation increased pituitary and exposed to ethanol for 24 hours and Drug Abuse. Boca Raton, FL: CRC Press, 1994, weight, pituitary prolactin mRNA (Sarkar and Boyadjieva 2007). pp.365–378. and protein content, and prolactin These and other studies (Gavaler Mello, N.K.; Bree, M.P.; Mendelson, J.H.; et al. Alcohol plasma levels in female rats compared 1994; Mello et al. 1989; Seki et al. self-administration disrupts reproductive function in with control animals (Gangisetty et 1991; Valimaki et al. 1984) clearly female macaque monkeys. Science 221(4611):677– al. 2015). These changes are asso- have demonstrated that chronic 679, 1983. PMID: 6867739 ciated with decreased D2R mRNA alcohol consumption is a positive Mello, N.K.; Mendelson, J.H.; and Teoh, S.K. Neuroendocrine and protein. This decrease seems to consequences of alcohol abuse in women. Annals of risk factor for the development of the New York Academy of Sciences 562: 211–240, be related to reduced activity of the prolactinomas and hyperprolactin- 1989. PMID: 2662859 gene resulting from epigenetic mod- emia. Common manifestations of Mello, N.K.; Mendelson, J.H.; Bree, M.P.; and Skupny, ifications of the D2R gene. Thus, hyperprolactinemia in women include A. Alcohol effects on naloxone-stimulated luteinizing fetal ethanol exposure increased lack of menstrual cycles (i.e., amen- hormone, follicle-stimulating hormone and prolactin methylation of a regulatory element orrhea) and excessive or spontaneous plasma levels in female rhesus monkeys. Journal of Pharmacology and Experimental Therapeutics 245(3): (i.e., the promoter) of the D2R secretion of milk (i.e., galactorrhea). 895–904, 1988. PMID: 3133465 gene, thereby reducing transcrip- Men with hyperprolactinemia typi- tion. In addition, ethanol exposure Oomizu, S.; Boyadjieva, N.; and Sarkar, D.K. Ethanol cally show hypogonadism, with and estradiol modulate alternative splicing of dopamine increased the mRNA levels for decreased sex drive, reduced sperm D2 receptor messenger RNA and abolish the inhibitory several methylating enzymes and production, and impotence, and action of on prolactin release from the enzymes called histone deacetylases may also exhibit breast enlargement pituitary gland. Alcoholism: Clinical and Experimental that modify the proteins (i.e., his- (i.e., gynecomastia), although they Research 27(6):975–980, 2003. PMID: 12824819 tones) around which the DNA is very rarely produce milk. Sarkar, D.K. Hyperprolactinemia following chronic wound, which also interfere with alcohol administration. Frontiers of Hormone Research 38:32–41, 2010. PMID: 20616493 transcription (Gangisetty et al. 2015). The role of these processes in ethanol- References Sarkar, D.K., and Boyadjieva, N.I. Ethanol alters induced modifications of prolactin production and secretion of -regulated Ben-Jonathan, N., and Hnasko, R. Dopamine as a growth factors that control prolactin-secreting tumors in the pituitary. levels was confirmed by the finding prolactin (PRL) inhibitor. Endocrine Reviews 22(6): Alcoholism: Clinical and Experimental that treatment with agents that 724–763, 2001. PMID: 11739329 Research 31(12):2101–2105, 2007. PMID: 18034699 prevent DNA methylation and/or Chaturvedi, K., and Sarkar, D.K. Alteration in G proteins Seilicovich, A.; Rubio, M.; Duvilanski, B.; et al. Inhibition histone deacetylase activity normal- and prolactin levels in pituitary after ethanol and estro- by naloxone of the rise in hypothalamic dopamine and ized D2R mRNA expression, pitu- gen treatment. Alcoholism: Clinical and Experimental serum prolactin induced by ethanol. Psychopharmacology itary weight, and plasma prolactin Research 32(5):806–813, 2008. PMID: 18336630 (Berlin) 87(4):461–463, 1985. PMID: 3001809 levels in fetal alcohol–exposed rats De, A.; Boyadjieva, N.; Oomizu, S.; and Sarkar, D.K. Seki, M.; Yoshida, K.; and Okamura, Y. [A study on (Gangisetty et al. 2015). Ethanol induces hyperprolactinemia by increasing hyperprolactinemia in female patients with prolactin release and lactotrope growth in female rats. alcoholics] [Article in Japanese]. Arukoru Kenkyuto Ethanol affects prolactin levels not Alcoholism: Clinical and Experimental Research Yakubutsu Ison 26(1):49–59, 1991. PMID: 2069537 only through its impact on D2R but 26(9):1420–1429, 2002. PMID: 12351938 Sengupta, A., and Sarkar, D.K. Roles of dopamine 2 also through changes in the produc- De, A.; Boyadjieva, N.; Pastorcic, M.; and Sarkar, D. receptor isoforms and G proteins in ethanol regulated tion and secretion of growth factors Potentiation of the mitogenic effect of estrogen on the prolactin synthesis and lactotropic cell proliferation. in the pituitary that help control lac- pituitary-gland by alcohol-consumption. International PLoS One 7(9):e45593, 2012. PMID: 23029123 Journal of Oncology 7(3):643–648, 1995. PMID: 21552885 totropic cell proliferation. Specifically, Soyka, M.; Gorig, E.; and Naber, D. Serum prolactin ethanol exposure of ovariectomized Dees, W.L., and Kozlowski, G.P. Differential effects of increase induced by ethanol—a dose-dependent ethanol on luteinizing hormone, follicle stimulating effect not related to stress. Psychoneuroendocrinology rats for 2 to 4 weeks decreased the hormone and prolactin secretion in the female rat. 16(5):441–446, 1991. PMID: 1805295 levels of growth-inhibitory molecules Alcohol 1(6):429–433, 1984. PMID: 6443069 Valimaki, M.; Pelkonen, R.; Harkonen, M.; and Ylikahri, R. (e.g., transforming growth factor Gangisetty, O.; Wynne, O.; Jabbar, S.; et al. Fetal Hormonal changes in noncirrhotic male alcoholics beta-1 [TGFβ-1]) and increased the alcohol exposure reduces dopamine receptor D2 and during ethanol withdrawal. Alcohol and Alcoholism levels of growth-stimulatory factors, increases pituitary weight and prolactin production via 19(3):235–242, 1984. PMID: 6508878

e-4 | Vol. 38, No. 2 Alcohol Research: Current Reviews the hypothalamus, hippocampus, and switch off the stress response (Myers (i.e., medulla) of the .1 pituitary. This binding decreases CRF, et al. 2012; Wynne and Sarkar 2013). These hormones facilitate an imme- AVP, and ACTH production (figure 1). A second component of the stress diate reaction by triggering physio- An additional negative feedback mech- response is the fight-or-flight response logical changes, such as increased anism involves the BEP produced from of the sympathetic nervous system, rate and respiration, and pro- POMC, which is synthesized in the which acts as the first line of defense vide the body with a burst of energy ventromedial arcuate nucleus of the against stressors. In a stressful situation, through the release of sugar (i.e., a brain region called the amygdala hypothalamus after stress activation. glucose) and fat into the blood- sends out a stress signal to the hypo- stream as energy sources that help CRF release by cells from the PVN of thalamus, which induces the activation the hypothalamus activates this BEP the body to respond to the stressors of the sympathetic nervous system and fight off the threat. This part of synthesis and release, which then inhib- and the release of the neurotransmitter its further CRF release, creating a neg- the stress response also is regulated acetylcholine from preganglionic sym- by BEP produced from POMC in ative feedback cycle (Plotsky et al. 1991). pathetic nerves. Acetylcholine, in turn, the hypothalamus, which not only These feedback processes help to main- stimulates the release of the catechol- tain the cortisol concentration within amine hormones epinephrine and 1 also is released from postganglionic neurons of a narrow physiological window and norepinephrine from the inner layer the sympathetic nervous system.

Table Summary of Important Hormones, Their Sites of Production, the Hormone System They Belong to, and Their Main Functions or Target Organs

Site of Production Hormone Hormone System Main Function or Target Organ

Row 2 TD1 Corticotropin-releasing factor Hypothalamic–pituitary–adrenal axis Anterior pituitary gland

R3 TD1 Luteinizing hormone–releasing hormone Hypothalamic–pituitary–gonadal axis Anterior pituitary gland

Rw4 TD1 Thyrotropin-releasing hormone Hypothalamic–pituitary–thyroid axis Anterior pituitary gland Hypothalamus Growth hormone–releasing hormone Growth hormone/insulin-like growth factor-1 Anterior pituitary gland Growth hormone/insulin-like growth factor-1, R6 TD1 Somatostatin Anterior pituitary gland Hypothalamic–pituitary–thyroid axis R7 Td1 Dopamine Prolactin Anterior pituitary gland R8 TD1 Adrenocorticotropic hormone Hypothalamic–pituitary–adrenal axis R9 TD1 Thyroid-stimulating hormone Hypothalamic–pituitary–thyroid axis Thyroid

Anterior Pituitary Follicle-stimulating hormone Hypothalamic–pituitary–gonadal axis Gonads (ovaries, testes) Gland Luteinizing hormone Hypothalamic–pituitary–gonadal axis Gonads (ovaries, testes) R10 TD1 R11 Td1 Growth hormone Growth hormone/insulin-like growth factor-1 Growth and repair of all cells R12 Td1 Prolactin Prolactin Breast

Hypothalamus/ Arginine vasopressin Hypothalamic–pituitary–adrenal axis Blood vessels and Posterior Pituitary Uterus, mammary glands, male Oxytocin Oxytocin Gland R13 Td1 reproductive organs Body stress, metabolism, Adrenal Glands Glucocorticoids (cortisol, corticosterone) Hypothalamic–pituitary–adrenal axis glucose maintenance Female reproductive glands (Follicle) Estrogen (estrone, estradiol, estriol) Hypothalamic–pituitary–gonadal axis and tissues, bones, heart Ovary Maintenance of pregnancy and Hypothalamic–pituitary–gonadal axis (Corpus Luteum) preparation of breast tissue Testes Hypothalamic–pituitary–gonadal axis Masculinity, sperm production, bone Thyroxine (T4) Heart rate, temperature, Thyroid Hypothalamic–pituitary–thyroid axis Triiodothyronine (T3) metabolism Insulin Pancreas Lower blood sugar Pancreas Pancreas Increase blood sugar

Pathophysiology of the Effects of Alcohol Abuse on the Endocrine System | e-5 modulates CRH release but also can Additional studies of chronic alcohol the HPA axis stress response, gluco- help decrease the stress response and administration found an association corticoid signaling, and the BEP and return the body to a state of homeo- between HPA axis response and level opioid system also may be involved stasis.2 BEP binds with high specificity of alcohol consumption (Richardson in the predisposition for, as well as to different receptors (i.e., μ- and et al. 2008). In these analyses, the HPA development and progression of, AUD. δ-opioid receptors), thereby inhibiting response after several weeks of daily However, a discussion of this evidence the sympathetic nervous system response 30-minute self-administration of alcohol and the proposed mechanisms is beyond to stress. BEP produced from pituitary was highest in the animals with the the scope of this article. POMC in response to hypothalamic lowest level of consumption (<0.2 mg/ CRF and AVP, in contrast, circulates kg/session) and most blunted in animals The HPA Axis, Alcohol, and the with the highest level of consumption in the periphery and has less impact on Immune System sympathetic nervous system function (~1.0 mg/kg/session). Furthermore, (Wynne and Sarkar 2013). chronic alcohol exposure was associated AUDs often are associated with with anxiety-producing–like (i.e., chronic systemic inflammation and anxiogenic-like) behaviors (King et al. high levels of circulating proinflamma- Alcohol’s Effects on the HPA Axis 2006). These studies clearly indicate that tory cytokines. Alcohol may induce Considerable lines of evidence indicate chronic exposure to alcohol attenuates inflammation through both direct that alcohol consumption affects the basal ACTH and corticosterone levels and indirect mechanisms. For example, stress-response pathways and the HPA and increases anxiogenic-like behaviors. alcohol metabolism results in the pro- axis. Acute exposure to alcohol activates Various mechanisms have been duction of reactive oxygen species the HPA axis, leading to a dose-related proposed for the blunted HPA axis (ROS) and cell damage that can trigger increase in circulating ACTH and responsiveness to chronic alcohol con- the production of proinflammatory glucocorticoids and inducing anxiolytic- sumption. Several of these focus on cytokines (Haorah et al. 2008). Alcohol the relationship between alcohol and like responses (Richardson et al. 2008; also may damage the bacterial flora in CRF expression: Varlinskaya and Spear 2006). Jenkins the gut as well as the intestinal walls, and Connolly (1968) showed that leading to the release and transfer into • Alcohol dependence has been the blood of bacterial lipopolysaccha- plasma cortisol levels significantly shown to be associated with a rides, which play a key role in alcohol- increased in healthy subjects at alcohol decrease in CRF mRNA expression mediated inflammation (Purohit et al. doses exceeding 100 mg/dL. Similarly, (Richardson et al. 2008) as well as 2008; Wang et al. 2010). A bidirec- healthy men who were in the top per- reduced responsiveness of the pitu- tional interaction between the HPA centile of self-reported alcohol con- itary to CRF (Sarnyai et al. 2001). axis and the immune system also may sumption had higher levels of excreted contribute to alcohol-induced inflam- cortisol in urine (Thayer et al. 2006). • Animal studies using mice that matory reactions. Thus, by binding to In addition, these researchers reported produced no CRF (i.e., CRF their receptors, glucocorticoids can that the inhibitory control of the HPA knockout mice) found that when interfere with certain signaling pathways axis was impaired in heavy drinkers. the animals were exposed to ethanol that repress transcription of many Finally, people with a family history of (in a continuous- or a limited-access inflammatory proteins (Barnes 2006). alcohol use disorder (AUD) exhibited paradigm), they consumed twice as In addition, CRF and ACTH have hyperresponsiveness of the stress response much ethanol as their counterparts immuno-potentiating and proinflam- mediated by the HPA axis (Uhart et with a functional CRF gene. In matory properties (figure 1) (Besedovsky al. 2006; Zimmermann et al. 2004). addition, the knockout mice exhib- and del Rey 1996). Conversely, inter- Similar findings were obtained in ited a reduced sensitivity to the leukins (ILs) and cytokines produced animal studies, where acute ethanol locomotor-stimulant and rewarding by activated immune cells (i.e., macro- administration to rats increased plasma effects of ethanol (Olive et al. 2003). phages) can act on the HPA axis and ACTH and corticosterone levels by induce CRF and ACTH secretion in enhancing CRF release from the hypo- • Mice lacking a functional CRF1 an adaptive feedback mechanism thalamus (Rasmussen et al. 2000; receptor progressively increased (Bateman et al. 1989; Blalock and Rivier and Lee 1996). Neutralization their ethanol intake when subjected Costa 1989). This bidirectional inter- of circulating CRF using specific anti- to repeated stress; this effect seemed action between the HPA axis and bodies inhibited ethanol’s stimulatory to persist throughout their life immune function is essential for sur- actions on ACTH and corticosterone (Sillaber et al. 2002). vival and for maintaining the body’s secretion (Rivier and Lee 1996). homeostasis. However, excessive alcohol

2 Note that BEP also acts as an endogenous opioid peptide with Numerous studies have suggested that exposure compromises HPA axis and pain-relieving (i.e., antinociceptive) effects. genetically determined differences in immune functions by altering cytokine e-6 | Vol. 38, No. 2 Alcohol Research: Current Reviews levels in a variety of tissues, including the brain, with the specific effect on cytokine production depending on the Stress length of exposure. For example, acute exposure to ethanol is associated with

GR suppressed production of certain cyto- Alcohol Hippocampus Amygdala kines (e.g., tumor necrosis factor alpha MR [TNFα] and IL-1β) (Pruett et al. 2004), Cytokines Hypothalamus whereas chronic exposure induces an PNS increase in the production of proin- EP CRF GR flammatory cytokines, such as TNFα (AVP) (Mandrekar et al. 2009; Nagy 2004). SNS The increase in innate immune signal- ing molecules in the brain associated Pituitary POMC with chronic alcohol consumption can producing affect cognitive function and promote cells GR alcohol use behaviors. Acetylcholine It has been speculated that dysregu- ACTH Adrenal gland lations of HPA axis function caused by chronic alcohol exposure mediates these effects on the immune system (figure 1). Several studies clearly have Catecholamines Corticosteroid demonstrated that ethanol exposure during the developmental period Lymphoid organs Acute Chronic induced neurotoxicity and permanent Anti-in ammatory - CRF, ACTH, and - CRF, ACTH, and corticosteroid corticosteroid impairments in the HPA axis that cytokines (IL-18, INF-γ) - “Fight or ight” stress - Blunted stress were associated with immune dysfunc- In ammatory reponse reponse tion (Hellemans et al. 2010; Kuhn cytokines (IL-1α, IL-1β, - Glucose - Immune disfunction IL-6, IL-12, TNFα) metabolism - Alcohol use disorder and Sarkar 2008; Sarkar et al. 2007). - Immune suppression Macrophages residing in the brain (i.e., microglia) play an important role in these neurotoxic effects of alcohol Figure 1 Alcohol’s effects on the hypothalamic–pituitary–adrenal (HPA) axis and the stress (Boyadjieva and Sarkar 2010; Fernandez- response. Alcohol can stimulate neurons in the paraventricular nucleus (PVN) of Lizarbe et al. 2009). the hypothalamus to release corticotropin-releasing factor (CRF) and arginine vaso- pressin (AVP). Stress sensed in the amygdala also elicits a similar activation of this stress response pathway. In the anterior pituitary, CRF stimulates the production of Alcohol and the HPG Axis (POMC), which serves as the prohormone for adrenocortico- tropic hormone (ACTH). AVP potentiates the effects of CRF on ACTH release from the anterior pituitary. ACTH stimulates cells of the cortical portion of adrenal glands Normal Functioning of the HPG Axis to produce and release glucocorticoid hormones (i.e., cortisol). High levels of glucocorticoids inhibit CRF and ACTH release through a negative feedback by Reproductive function is regulated by binding to glucocortiocoid receptors (GRs) and mineralocorticoid receptors (MRs) a cascade of events that are under the in various brain regions. Neurons in the arcuate nucleus of the hypothalamus control of the HPG axis. The hypothal- release β-endorphin (BEP), which also regulates CRF release. BEP also acts on amus produces and secretes LHRH, the autonomous nervous system and inhibits the sympathetic nervous system (SNS) also called gonadotropin-releasing hor- stress response. CRF, ACTH, and glucocorticoids also act on different organs of the immune system and stimulate cytokine production and release into the general mone, into the hypothalamic–pituitary circulation. These cytokines then reach the brain where they trigger a neuroimmune portal network. At the anterior pitu- response that sensitizes the stress-response pathway. Acute exposure to alcohol itary, LHRH stimulates the production stimulates the HPA-axis stress response and induces suppression of cytokine pro- and secretion of FSH and LH from duction. In contrast, chronic exposure to alcohol induces a blunted HPA-axis stress gonadotropic cells into the general cir- response characterized by an absence of negative feedback control of this pathway culation. These gonadotropins regu- and an increase in proinflammatory cytokines, such as interleukin-6 (IL-6) and late the development of follicles (i.e., tumor necrosis factor alpha (TNFα), leading to stress intolerance, immune dysfunc- folliculogenesis) in females and of tion and alcohol use disorder. sperm (i.e., spermatogenesis) in males. Moreover, each month during the

Pathophysiology of the Effects of Alcohol Abuse on the Endocrine System | e-7 follicular phase of the menstrual cycle, 3.84 drinks per day) and 60 percent drinkers exhibited excessive levels of FSH stimulates the development of a of heavy (i.e., about 7.81 drinks per prolactin in the blood (i.e., hyperpro- dominant follicle in the ovary, which day) healthy, nondependent drinkers lactinemia) (Mendelson et al. 1988). then produces and secretes the hor- exhibited significant disturbances of Studies have shown that alcohol intake mone estradiol. The rise in estradiol their reproductive hormones and men- consistently induces an increase in through a feedback mechanism is strual cycle compared with occasional estradiol levels in humans (Mendelson responsible for the surge in LH and drinkers (i.e., about 1.22 drinks per and Mello 1988; Muti et al. 1998) FSH levels that occurs in the middle day). In addition, social drinkers had and rodents (Emanuele et al. 2001a), of the menstrual cycle. LH then induces anovulatory cycles, and 3 of 5 heavy possibly as a result of decreased steroid ovulation and the development of the corpus luteum, which in turn produces and secretes progesterone, an import- Alcohol ant hormone that helps maintain exposure pregnancy. In the testes, in contrast, LH stimulates testosterone production and release, whereas FSH controls Hypothalamus spermatogenesis. HPG axis function LHRH is controlled through feedback mecha- nisms, where testosterone, estrogen, and progesterone control their own production by acting on the hypothal- + Pituitary gland amus and anterior pituitary to inhibit or stimulate the release of LHRH, LH/FSH LH, and FSH (Sarkar 1983).

Alcohol’s Effects on the HPG Axis Estradiol/ Gonads Testosterone Numerous studies have documented progesterone alcohol’s diverse deleterious effects on Acute Chronic - Irregular menstrual cycle - Irregular menstrual cycle the HPG axis and its hormones (figure - LHRH, LH, and FSH - Decreased fertility 2). The resulting HPG dysfunction - Testosterone - Hypogonadism observed in people with AUD can - Estradiol - LHRH and LH be associated with diverse outcomes, - Progesterone - FSH including a decreased libido, infertility, - Testosterone - Estradiol and gonadal atrophy. It also is important - Progesterone to note that these deleterious effects are not limited to adult drinkers but may also affect adolescents in puberty Figure 2 Alcohol’s effects on the hypothalamic–pituitary–gonadal (HPG) axis. Neurons in who begin to consume alcohol. For more the hypothalamus release luteinizing hormone–releasing hormone (LHRH) to the information, see the sidebar “Alcohol’s hypophyseal-portal blood system. LHRH then stimulates the secretion of gonadotropins (i.e., LH and FSH). During the ovary’s follicular phase, FSH stimulates the development Effects on the Hypothalamic–Pituitary– of a dominant follicle, which produces and secretes estradiol. Estradiol then stimulates Gonadal Axis During Puberty.” an LH and FSH surge during midcycle of the menstrual cycle. LH stimulates ovulation In women, alcohol use can cause a and the development of the corpus luteum, which then produces and secretes proges- multitude of reproductive disorders, terone. In the testis, LH stimulates testosterone production and release, while FSH such as irregular menstrual cycles, controls spermatogenesis. HPG axis function is controlled through feedback loop absence of ovulation (i.e., anovulation), mechanisms. Testosterone inhibits LHRH, LH, and FSH secretion through negative increased risk of spontaneous abor- feedback, whereas estradiol and progesterone both can have negative- and positive- feedback actions, depending on the stage of the ovarian cycle, and can inhibit tions, and early menopause. Alcohol or stimulate the release of LHRH, LH, and FSH. Acute alcohol exposure results in intake, even as little as five drinks per increased LHRH, LH, FSH, and estradiol and decreased testosterone and progesterone. week, was associated with decreased Chronic alcohol exposure, in contrast, induces a decrease in LHRH, LH, testosterone, fecundability in healthy women ages and progesterone and an increase in estradiol and FSH. These alcohol-induced 20–35 (Jensen et al. 1998). Other hormonal dysregulations cause a multitude of reproductive disorders, such as menstrual studies (Mendelson et al. 1988) found cycle irregularity, decreased fertility, and hypogonadism. that 50 percent of social (i.e., about e-8 | Vol. 38, No. 2 Alcohol Research: Current Reviews catabolism (Sarkola et al. 1999). These gonadism even in the absence of that influence how cells use different increased estradiol levels could in part liver disease. energetic compounds (i.e., proteins, explain alcohol’s negative effects on fats, and carbohydrates). When circu- menstrual cycle regularity. Moreover, • In men with AUD and cirrhosis, a lating levels of are chronic alcohol has inhibitory actions decrease in IGF-1 bioavailability as low, the hypothalamus responds by on LHRH-producing neurons. Thus, a result of liver disease contributes releasing TRH, which then stimulates exposure to 100 mM ethanol directly at least in part to the elevated circu- thyrotropic cells in the anterior pitu- inhibited LHRH release from incu- lating levels of estradiol and estrone itary to produce and secrete TSH. bated medial basal hypothalamic (Martinez-Riera et al. 1995) and This hormone, in turn, promotes the sections, and this effect was reversed the development of hypogonadism synthesis and secretion of T4 and T3 by naltrexone (Lomniczi et al. 2000). (Castilla-Cortazar et al. 2000) since from the follicular cells of the thyroid These results suggest that alcohol’s IGF-1 can stimulate testosterone gland. Iodine is essential to T4 and T3 effect on LHRH release involves the synthesis and spermatogenesis production, with T4 containing four, stimulation of BEP-releasing neurons, (Roser 2008). and T3 containing three, iodine atoms. which prevent LHRH release by Although both T4 and T3 are secreted inhibiting nitric oxide synthase. Other • ROS produced during alcohol by the thyroid following TSH stimula- studies have shown that long-term metabolism may cause cell damage in tion, 80 percent of circulating T3 is moderate alcohol consumption can the testes (Emanuele et al. 2001b). derived from the conversion of T4 by decrease the number and quality of a The testicular alcohol-inducible enzymes called deiodinases in the liver. woman’s oocytes (i.e., ovarian reserve), cytochrome P450 2E1, which is Like the HPA and HPG axes, the which was associated with increased involved in the generation of ROS HPT axis is regulated by negative- FSH levels (Li et al. 2013). as well as hydroxyl ethyl free radicals, feedback loops where T4 and T3 act was shown to be elevated in testes Extensive research in animals and back on the hypothalamus and the of rats chronically exposed to etha- humans also has documented the pituitary to control their own release nol (Shayakhmetova et al. 2013). deleterious effects of alcohol on male by inhibiting TRH and TSH secretion. reproductive function, including • The alcohol metabolite acetaldehyde reduced testosterone levels (figure 2). can disrupt testosterone production Alcohol’s Effects on the HPT Axis Acute alcohol intake decreased the by inhibiting protein kinase C, a circulating levels of LH and testoster- key enzyme in testosterone synthe- Numerous studies have described one as a result of diminished release sis (Chiao and Van Thiel 1983). HPT axis dysfunction in people with of hypothalamic LHRH (Cicero et AUD (see figure 3). For example, al. 1982; Dees et al. 1983; Rowe • Nitric oxide, which is synthesized these individuals consistently exhibit et al. 1974). In contrast, chronic in the testes by nitric oxide synthase, a reduced or absent response of TSH alcohol consumption significantly is another proposed player in the to TRH (Sellman and Joyce 1992). increased FSH, LH, and estrogen alcohol-induced reduction of tes- A blunted TSH response also was levels but decreased testosterone and tosterone production. Inhibition of observed during early withdrawal and progesterone levels in men with AUD nitric oxide synthase prevents the was positively correlated with severity compared with men without AUD alcohol-induced decrease in testos- of withdrawal symptoms; in fact, it (Muthusami and Chinnaswamy 2005). terone (Adams et al. 1992). may be an important predictor of The AUD group also had significantly relapse (Pienaar et al. 1995). However, lower semen volume, sperm count, conflicting changes in peripheral thy- motility, and number of morpho- roid hormones in response to alcohol logically normal sperm (Muthusami Alcohol and the HPT Axis exposure and withdrawal have been and Chinnaswamy 2005). Several reported. T4 and T3 circulate in two mechanisms may contribute to alco- forms, a protein-bound inactive form hol’s effects on the various hormones and a free, readily available active form. involved in the male HPG axis: Normal Functioning of the HPT Axis Some studies found normal concentra- The HPT axis is responsible for main- tions of total plasma T4 (tT4) during • The activity of the enzyme aro- taining normal circulating levels of the early withdrawal (Majumdar et al. 1981), matase, which converts androgens thyroid hormones thyroxin (T4) and whereas others found significantly to , especially in the liver, its active form, triiodothyronine (T3). reduced tT4 levels (Valimaki et al. is increased by ethanol (Purohit These two hormones affect every cell 1984). The levels of free T4 and T3, 2000). This mechanism may explain and organ in the body, primarily regu- however, were lower in people with why alcohol abuse results in hypo- lating different metabolic processes AUD during withdrawal and early

Pathophysiology of the Effects of Alcohol Abuse on the Endocrine System | e-9 Alcohol’s Effects on the Hypothalamic–Pituitary–Gonadal Axis During Puberty

Little research has assessed the disruptions of puberty-related significant decline in circulating effects of alcohol use on the hypo- processes. Bo and colleagues (1982) IGF-1, LH, and estrogen and was thalamic–pituitary–gonadal (HPG) reported that alcohol administration most pronounced at 32 months of axis during puberty in humans. to prepubertal female rats induced a age. The reduced hormone levels Initiation and progression of puberty marked delay in vaginal opening. affected the monthly pattern of are controlled by signals from the This delay could be prevented by menstruation in the rhesus macaques central nervous system that stimulate naltrexone, an antagonist of the opioid and induced a lengthening of the the pulsatile diurnal secretion of receptors (Emanuele et al. 2002), intervals between menses in the alcohol- luteinizing hormone-releasing suggesting that alcohol’s effects exposed monkeys (Dees et al. 2000). hormone (LHRH) from the hypo- during puberty partly may result Taken together, these findings thalamus into the hypothalamic– from an increased opioid restraint clearly show that the activities of the pituitary portal system (Sarkar and on the normal progression of puber- HPG and GH/IGF-1 axes during Fink 1979; Sarkar et al. 1976). tal processes. Another proposed puberty are closely interconnected. LHRH then triggers the pituitary to mechanism for the alcohol-induced This is further demonstrated by secrete luteinizing hormone (LH) decrease in LH secretion during observations that estrogen can stim- and follicle-stimulating hormone puberty is that even though the ulate GH secretion (Mauras et al. (FSH), resulting in subsequent ovar- hypothalamus produced more LHRH, 1996) and that IGF-1 can stimulate ian maturation (Plant 2015). During the release of the hormone to the LHRH secretion (Hiney and Dees childhood, the LHRH surge is pituitary gland was diminished 1991), suggesting that activation of repressed through inhibitory signals (Dees and Skelley 1990). This effect the HPG axis leads to both sexual in the hypothalamus mediated by may result, at least in part, from maturation and a growth spurt γ-aminobutyric acid and opioid altered release of E2 mediated through estrogen-induced peptides (Terasawa and Fernandez (Hiney and Dees 1991), which stimulation of the GH/IGF-1 axis. 2001). During puberty, however, normally mediates stimulation of Therefore, alcohol-induced distur- LHRH release is triggered by a vari- LHRH release by norepinephrine. bances in the activity of the HPG ety of stimulatory agents, such as In addition, alcohol exposure induc- axis during this critical stage of insulin-like growth factor-1 (IGF-1) es an increase in hypothalamic human development could have (Hiney and Dees 1991), norepi- growth hormone (GH)-releasing far-reaching consequences on repro- nephrine (Sarkar et al. 1981), hormone content that also is associ- ductive function as well as growth (Dearth et al. 2000), transforming ated with diminished release of the that might persist through adult life. growth factor alpha (Ojeda et al. 1990), hormone and, therefore, reduced and kisspeptins (Navarro et al. 2005). ability to stimulate GH secretion Human studies have documented from the anterior pituitary (Dees References that moderate alcohol consumption and Skelley 1990). These effects of induces disruptions in normal alcohol exposure on GH were asso- Block, G.D.; Yamamoto, M.E.; Mallick, A.; and Styche, A. Effects on pubertal hormones by ethanol abuse in hormone levels during puberty, ciated with a decrease in circulating adolescents. Alcoholism: Clinical and Experimental including a decrease in estrogen IGF-1, which could explain the Research 17:505, 1993. levels in adolescent girls that was growth impairments observed in Bo, W.J., Krueger, W.A.; Rudeen P.K.; and Symmes, S.K. sustained for long periods of time animals exposed to alcohol (Srivastava Ethanol-induced alterations in the morphology and (Block et al. 1993). Similar, alcohol et al. 1995). In studies in rhesus function of the rat ovary. Anatomical Record abuse induced a significant reduc- macaques, administration of alcohol 202(2):255–260, 1982. PMID: 7199834 tion in testosterone, LH, and FSH (2 g/kg) for 12 months to immature Dearth, R.K.; Hiney, J.K.; and Dees, W.L. Leptin acts levels in adolescent boys (Diamond females resulted in suppression of centrally to induce the prepubertal secretion of lutein- izing hormone in the female rat. Peptides 21(3):387– et al. 1986). Animal studies on rodents the nightly increase in circulating 392, 2000. PMID: 10793221 and monkeys have helped to under- GH that occurs during late juvenile Dees, W.L., and Skelley, C.W. Effects of ethanol during stand and identify the mechanisms development (Dees et al. 2000). the onset of female puberty. Neuroendocrinology involved in these alcohol-mediated This effect was associated with a 51(1):64–69, 1990. PMID: 2106089

e-10 | Vol. 38, No. 2 Alcohol Research: Current Reviews Alcohol’s Effects on the Hypothalamic–Pituitary–Gonadal Axis During Puberty (continued)

Dees, W.L.; Dissen, G.A.; Hiney, J.K.; et al. Alcohol Mauras, N.; Rogol, A.D.; Haymond, M.W.; and Veldhuis, Sarkar, D.K., and Fink, G. Mechanism of the first spon- ingestion inhibits the increased secretion of puberty- J.D. Sex steroids, growth hormone, insulin-like growth taneous gonadotrophin surge and that induced by related hormones in the developing female rhesus factor-1: Neuroendocrine and metabolic regulation in pregnant mare serum and effects of neonatal andro- monkey. Endocrinology 141(4):1325–1331, 2000. puberty. Hormone Research 45(1–2):74–80, 1996. gen in rats. Journal of Endocrinology 83(3):339–354, PMID: 10746635 PMID: 8742123 1979. PMID: 395267 Diamond, F., Jr.; Ringenberg, L.; MacDonald, D.; et al. Navarro, V.M.; Castellano, J.M.; Fernandez-Fernandez, Sarkar, D.K.; Chiappa, S.A.; Fink, G.; and Sherwood, N.M. Effects of drug and alcohol abuse upon pituitary- R.; et al. Characterization of the potent luteinizing Gonadotropin-releasing hormone surge in pro-oestrous testicular function in adolescent males. Journal of hormone-releasing activity of KiSS-1 peptide, the natu- rats. Nature 264(5585):461–463, 1976. PMID: 794737 Adolescent Health Care 7(1):28–33, 1986. PMID: ral ligand of GPR54. Endocrinology 146(1):156–163, 2935515 2005. PMID: 15375028 Srivastava, V.; Hiney, J. K.; Nyberg, C.L.; and Dees, W.L. Effect of ethanol on the synthesis of insulin-like Emanuele, N.; Ren, J.; LaPaglia, N.; et al. EtOH disrupts Ojeda, S.R.; Urbanski, H.F.; Costa, M.E.; et al. Involve- growth factor 1 (IGF-1) and the IGF-1 receptor in late female mammalian puberty: Age and opiate dependence. ment of transforming growth factor alpha in the release prepubertal female rats: A correlation with serum Endocrine 18(3):247–254, 2002. PMID: 12450316 of luteinizing hormone-releasing hormone from the IGF-1. Alcoholism: Clinical and Experimental Research developing female hypothalamus. Proceedings of the Hiney, J.K., and Dees, W.L. Ethanol inhibits luteinizing 19(6):1467–1473, 1995. PMID: 8749812 National Academy of Sciences of the United States of hormone-releasing hormone release from the America 87(24):9698–9702, 1990. PMID: 2263621 Terasawa, E., and Fernandez, D. L. Neurobiological median eminence of prepubertal female rats in vitro: Investigation of its actions on norepinephrine and Plant, T.M. Neuroendocrine control of the onset of mechanisms of the onset of puberty in primates. prostaglandin-E2. Endocrinology 128(3):1404–1408, puberty. Frontiers in Neuroendocrinology 38:73–88, Endocrine Reviews 22(1):111–151, 2001. PMID: 1991. PMID: 1999162 2015. PMID: 25913220 11159818 abstinence compared with nonalcoholic that the number of TRH receptors Baumgartner and colleagues (1997) healthy control subjects (Hegedus et in the pituitary is reduced as a result found that the activity of 5′II deiod- al. 1988). Additional analyses identified of increased TRH secretion (Aoun et inase was elevated in the frontal cortex a significant positive correlation between al. 2015; Herman 2002). A role for in both groups of rats. The activity of free T3 and alcohol-seeking behaviors increased TRH section in blunting 5-II deiodinase, however, was only in alcohol-dependent individuals the TSH response also is supported by inhibited in the amygdala of the rats (Aoun et al. 2015), supporting the observations that abstinent patients that were behaviorally dependent on hypothesis of a relationship between with AUD who had a severely blunted ethanol but was normal in the non- alcohol dependence and thyroid dys- TSH response to TRH showed increased dependent rats. As a result, intracellu- function. This thyroid dysfunction can levels of TRH in the cerebrospinal lar T3 levels were increased, and this recover after longer periods of absti- fluid (Adinoff et al. 1991). In rats, increase of intracellular T3 in the nence, with thyroid hormones and chronic alcohol exposure induced an amygdala might be involved in the the TSH response to TRH returning increase in TRH mRNA in neurons development of dependence behaviors to normal levels (Pienaar et al. 1995). of the PVN, but the animals no longer to alcohol (Baumgartner et al. 1997). Moreover, people who relapsed and responded to peripheral stimulation The role of changes in thyroid hormone returned to their alcohol-drinking of thyroid hormone secretion by expo- levels in the development of AUD also behavior again exhibited lower T4 and sure to cold (Zoeller et al. 1996). This is supported by findings that a func- T3 levels and a blunted TSH response suggests that chronic exposure to etha- tionally significant genetic variant (i.e., to TRH (Heinz et al. 1996). Animal nol induces dysfunction of the thyroid single nucleotide polymorphism) in studies have yielded similar results. gland, which then is no longer able to the deiodinase type II (D2) gene was Chronic exposure of adult male rats properly respond to TRH stimulation. associated with drinking behavior in to ethanol (10 percent weight/volume) Direct actions of ethanol on thyroid alcohol-dependent individuals (Lee et for 40 days induced a significant hormone metabolism, specifically on al. 2015). decrease in total T4 and T3, free T4 the activity of enzymes that catalyze Chronic alcohol use also had a direct and T3, as well as basal TSH levels the conversion of T4 to T3 (i.e., 5′II toxic effect on the thyroid gland, induc- (Mason et al. 1988). deiodinase) or inactivate T3 to 3,3′-T2 ing a dose-dependent significant reduc- Several mechanisms have been pro- (i.e., 5-II deiodinase), also have been tion in thyroid volume and increase in posed to explain the blunted TSH proposed. In a study comparing thyroid fibrosis in alcohol-dependent response to TRH in people with AUD. “behaviorally dependent” and ethanol- individuals (Hegedus et al. 1988). For example, several studies suggest exposed but “nondependent” rats, These effects were associated with

Pathophysiology of the Effects of Alcohol Abuse on the Endocrine System | e-11 reductions in total and free T3 levels, function or it stimulates IGF-1 pro- with a spike during puberty, when IGF-1 although the concentrations of total duction and secretion, especially from plays a critical role in reproductive- and free T4 as well as of TSH remained the liver, the principal production site organ maturation and long-bone unchanged (Hegedus et al. 1988). In for this factor. IGF-1 then is either growth. After puberty, the levels again contrast to these effects of chronic released into the general circulation, decrease slowly to reach the adult level. alcohol use on thyroid hormones, where it is bound to large circulatory IGF-1 can control its own secretion moderate alcohol consumption was binding proteins that regulate its through negative feedback at the level shown to reduce the risk of developing delivery to target tissues, or it mediates of the hypothalamus and pituitary by thyroid cancer. Several studies, includ- the anabolic effects of GH through reducing GH synthesis and release. ing the large NIH–AARP Diet and paracrine and autocrine mechanisms. Another hormone called somatosta- Health Study that followed 490,000 At birth, plasma IGF-1 levels are at tin, which is secreted from the PVN participants (males and females) over 50 percent of the adult levels and grad- of the hypothalamus, also acts on the 7.5 years, have shown a significant ually increase throughout childhood pituitary and inhibits GH secretion. reduction in the risk of developing all types of thyroid cancers in people who consumed two or more alcoholic drinks per day, especially in men. However, the effects differed between Alcohol different subtypes of thyroid cancer, exposure with a stronger inverse association for papillary thyroid cancer (relative risk = 0.58) compared with follicular thyroid Hypothalamus cancer (relative risk = 0.86) (Meinhold TRH et al. 2009). Furthermore, in a study of 4,649 healthy individuals who were exposed to increasing levels of alcohol, Knudsen and colleagues (2001) found Pituitary gland an association between a reduced thy- roid gland volume and a lower risk of TSH developing goiter or solitary nodules.

Alcohol and the GH/IGF-1 Axis Thyroid gland

T4, T3 Normal Functioning of the Acute Chronic GH/IGF-1 Axis - No effects on T3 and T4 - Blunted HPT-axis - Risk of thyroid cancer responsiveness Like the other hormone systems dis- - Free T3 and T4 cussed so far, the GH/IGF-1 axis is - T4 deiodination to T3 under the control of the hypothalamus. - Thyroid volume Growth hormone–releasing hormone - Thyroid brosis (GHRH) secreted from cells in the arcuate and ventromedial nuclei of the hypothalamus into the hypophyseal Figure 3 Alcohol’s effects on the hypothalamic–pituitary–thyroid (HPT) axis. Thyrotropin- portal system acts on somatotropic releasing hormone (TRH) released from neurons in the hypothalamus stimulates thyrotropic cells in the anterior pituitary to produce and secrete thyroid-stimulating cells in the anterior pituitary, stimulat- hormone (TSH). TSH then stimulates the synthesis and secretion of thyroxin (T4) ing them to synthesize and release GH and its active form, triiodothyronine (T3), from the follicular cells of the thyroid into the general circulation. GH is gland. Circulating T3 comes from conversion of T4 by enzymes called deiodinases essential to the growth of all tissues in in the liver. T3 and T4 can control their own release by negative feedback at the the body. It stimulates protein synthesis hypothalamus and the pituitary and inhibit TRH and TSH release. Acute alcohol and increases fat metabolism to pro- exposure has no effect on HPT-axis function. However, chronic alcohol exposure leads to vide the necessary energy for growth. a blunted TSH response to TRH, as well as to decreased free T3 and T4, decreased deio- GH binds to specific receptors on dination of T4 to T3, decreased thyroid volume, and increased thyroid fibrosis. target tissues and directly affects cell e-12 | Vol. 38, No. 2 Alcohol Research: Current Reviews Thus, the amount of GH secreted by Alcohol’s Effects on the of healthy men to ethanol (1.5 g/kg) the anterior pituitary is tightly regulated GH/IGF-1 Axis reduced the nightly peak of GH secre- tion (Valimaki et al. 1987). This effect by GHRH, IGF-1, and somatostatin. Numerous studies in both humans Together, GH and IGF-1 regulate did not seem to be mediated through and experimental animals have shown a direct action of ethanol on the pitu- important physiological processes in the that acute and chronic alcohol expo- itary that would have rendered it less body, such as pre- and postnatal growth sure has a variety of effects on the GH/ sensitive to GHRH, because intrave- and development (Giustina et al. 2008) IGF-1 axis (figure 4). For example, nous injection of exogenous GHRH and carbohydrate and lipid metabolism alcohol exposure reduces circulating induced an increase in GH secretion (Moller and Jorgensen 2009). GH and IGF-1 levels. Acute exposure in both ethanol-exposed (1 g/kg) and control men (Valimaki et al. 1987). Similarly, De Marinis and colleagues (1993), using an agent that can stimu- Alcohol late GHRH secretion (i.e., clonidine), exposure demonstrated that the pituitary response to GHRH was intact in abstinent alcoholics. Other studies evaluated Hypothalamus alcohol’s effects on numerous other factors that regulate GH secretion SS GHRH either through direct actions on the anterior pituitary or by modulating GHRH and somatostatin release from the hypothalamus. The analyses demon- Pituitary gland strated that during early abstinence, the GH response to these different GH secretagogues, which include such neurotransmitters as dopamine, nor- epinephrine, acetylcholine, γ-amino- butyric acid (GABA), and serotonin, also is altered. For example, men with AUD exhibited impairments both in Paracrine the serotonin-mediated stimulation of IGF-1/ and autocrine GH secretion (Coiro and Vescovi 1995) IGFBP actions and in ’s effect on basal and Acute Chronic hypoglycemia-induced GH secretion - GHRH and GH - GHRH and GH (Coiro and Vescovi 1998) during - IGF-1 - IGF-1 early abstinence. Moreover, intrave- - Anabolism nous injection of 10 mg diazepam, an - Insulin sensitivity allosteric modulator of GABA receptor - Growth retardation function, had no effect on GH secre- tion in men with AUD who had maintained a 5-week abstinence, whereas Figure 4 Alcohol’s effects on the growth hormone–insulin-like growth factor-1 (GH/IGF-1) control subjects without AUD showed axis. Growth hormone (GH)-releasing hormone (GHRH) secreted from neurons in a striking increase of GH secretion in the hypothalamus acts on somatotropic cells in the anterior pituitary and stimulates response to diazepam (Vescovi and the production and release of GH into the circulation. GH can act on target tissues Coiro 1999). Finally, alcohol inter- and directly affect their function or it can stimulate IGF-1 production and secretion from these target tissues, especially from the liver. IGF-1 then is either released feres with the normal release pattern into the general circulation, where it circulates bound to IGF binding proteins (IGFBP), of GH. The hormone normally is or it can mediate GH anabolic effects on target tissues through paracrine and secreted in a pulsatile manner, with autocrine actions. Through negative feedback at the hypothalamus and pituitary, the major secretory episode of GH IGF-1 can reduce GHRH and GH secretion. Somatostatin (SS), secreted in the occurring shortly after sleep onset, paraventricular nucleus of the hypothalamus, also acts on the pituitary and inhibits during the first period of slow-wave GH secretion. IGF-1 stimulates SS secretion. Acute and chronic alcohol exposure sleep. Studies have identified a consis- leads to decreased GHRH, GH, and IGF-1 secretion. tent and robust relationship between slow-wave sleep and increased GH

Pathophysiology of the Effects of Alcohol Abuse on the Endocrine System | e-13 Alcohol and Other Endocrine Tissues

In addition to the brain areas and Alcohol’s Effects on the Some studies have shown that mod- organs involved in the main hormone Endocrine Pancreas erate alcohol consumption improves axes in the body that are discussed in peripheral insulin sensitivity without this article, several other tissues also Heavy alcohol drinking can induce affecting insulin secretion from the development of inflammation of produce and secrete hormones that pancreatic β-cells (Avogaro et al. the pancreas (i.e., pancreatitis), most regulate crucial body functions, includ- 2004), whereas others determined commonly in acinar cells. However, a reduced basal insulin secretion ing the pancreas and fat (i.e., adipose) the inflammatory aspect of this dis- rate associated with a lower fasting tissue. Alcohol exposure also can ease also can damage islet cells and, plasma glucagon concentration interfere with these hormonal systems. therefore, the endocrine pancreas (Apte et al. 1997). Chronic alcohol (Bonnet et al. 2012). The beneficial consumption also is a risk factor for metabolic effects of moderate alcohol The Endocrine the development of pancreatic cancer, use on insulin sensitivity and glucose Pancreas with moderate to heavy consumption homeostasis therefore might explain increasing the risk both alone and the significant reduction in the risk The pancreas, which lies behind the in combination with other risk of development of type 2 diabe- , serves two major functions. factors, such as tobacco and obesity tes and of cardiovascular disorders First, acinar cells secrete digestive (de Menezes et al. 2013; Haas et al. (Avogaro et al. 2004; Bantle et al. enzymes into the small intestine, 2012). One type of pancreatic cancer 2008). thereby supporting . Second, called ductal adenocarcinoma has a Heavy alcohol consumption, in islet cells dispersed throughout the very aggressive behavior with a 5-year contrast, has several detrimental whole pancreas have an endocrine survival rate of less than 4 percent effects resulting in impaired control of blood glucose levels. In addition activity by producing hormones (i.e., (Welsch et al. 2006). Chronic alcohol consumption also to its effects on peripheral tissues, insulin and glucagon) that regulate is a known independent risk factor such as adipose tissue and the liver, blood glucose levels. These islet cells for the development of type 2 diabe- where it induces insulin resistance, α can be further subdivided into - and tes (Hodge et al. 1993; Holbrook et heavy drinking also negatively β α -cells. The -cells produce glucagon, al. 1990; Wei et al. 2000). This syn- affects pancreatic β-cell function. which raises blood glucose levels by drome is characterized by impaired In a study by Patto and colleagues stimulating the liver to metabolize glucose metabolism with high blood (1993), chronic drinkers exhibited a glycogen into glucose molecules and glucose levels (i.e., hyperglycemia) decreased insulin-secretion response to release the glucose into the blood. and peripheral insulin resistance. to glucose compared with the control In addition, glucagon stimulates The relationship between alcohol group. When the investigators mea- the adipose tissue to metabolize tri- consumption and the risk of type 2 sured the total integrated response glycerides into glucose, which then is diabetes is “U” shaped—that is, risk values for secreted insulin and for released into the blood. Conversely, is lower with moderate alcohol con- C-peptide1 following oral or intrave- the β-cells of the pancreas produce sumption than with either abstention nous glucose administration in these insulin, which lowers blood glucose or high alcohol consumption. Thus, two groups, both values were signifi- levels after a meal by stimulating the risk was reduced by 30 percent cantly lower in the chronic drinkers in moderate drinkers compared with the absorption of glucose by liver, compared with the control group. abstainers, whereas no risk reduction muscle, and adipose tissues and Moreover, in both groups the total was observed in heavy drinkers promoting the storage of glucose in consuming 48 grams of ethanol integrated response value for insulin the form of glycogen in these tissues. (i.e., 3 to 4 drinks) per day or more was significantly higher after oral The endocrine function of the pan- (Koppes et al. 2005). Moderate glucose administration than after creas primarily is controlled by both alcohol use may have protective 1 C-peptide is a chain of 31 amino acids that during insulin the sympathetic and the parasympa- effects by enhancing peripheral synthesis connects the two parts, or chains, of the insulin molecule in a precursor molecule. During final processing of thetic divisions of the autonomic insulin sensitivity (Conigrave et al. the insulin molecule, the C-peptide is removed to yield the nervous system. 2001; Tomie Furuya et al. 2005). functional insulin molecule with its two chains.

e-14 | Vol. 38, No. 2 Alcohol Research: Current Reviews Alcohol and Other Endocrine Tissues (continued) intravenous administration, suggest- receptors on pancreatic β-cells. This demonstrated that WAT is a dynam- ing a potentiating incretin2 effect could account at least for part of ically active endocrine organ that can on insulin secretion. These findings the alcohol-induced impairment in produce and secrete biologically active clearly indicate that chronic alcohol β-cell function, because activation of peptides and proteins called adipokines, exposure induces a β-cell dysfunc- GABA receptors in pancreatic β-cells which have autocrine, paracrine, and tion and not an enteroinsular increases insulin secretion (Bansal et endocrine actions. In fact, WAT may dysfunction, because the decrease al. 2011), has a protective and regen- be the largest endocrine organ in in insulin response compared with erative effect onβ -cells, and decreases mammals and can be found in indi- the control group also was observed cell apoptosis in cultured islet cells vidual pads in different locations when glucose was administered (Dong et al. 2006). The investigators throughout the body, both near other intravenously. further showed that acute treatment organs (i.e., viscerally) and under the Animal studies demonstrated that of cultured rat β-cells (i.e., the INS-1 skin (i.e., subcutaneously). Depending mice exposed to chronic alcohol for cell line) with 60 mM ethanol inter- on its location, WAT synthesizes and 8 to 10 weeks developed impairments fered with GABA-mediated cell acti- secretes different sets of adipokines in fasting glucose levels and exhib- vation as well as insulin secretion and (Coelho et al. 2013). Since the dis- ited an increase in β-cell apoptosis, that these effects could be prevented covery of leptin (Zhang et al. 1994), which were associated with dimin- by pretreating the cultured cells with multiple adipokines released by ished insulin secretion (Kim et al. GABA (100 mM), further support- WAT have been identified, including 2010). The investigators suggested ing the theory that alcohol’s effects hormones, growth factors, and cyto- that alcohol exposure led to a down- on β-cells and insulin production are kines (Coelho et al. 2013). regulation and inactivation of the mediated at least in part by GABA WAT also expresses several enzyme glucokinase, which acts as a signaling (Wang et al. 2014). In receptors that allow it to respond β-cell sensor for blood glucose levels. addition, experiments in another cul- to signals from other hormone sys- Glucokinase is involved in glucose tured β-cell line indicated that heavy tems and from the central nervous metabolism that leads to increased alcohol consumption may induce system. Through these different production of adenosine-triphosphate, β-cell dysfunction in type 2 diabetes communication pathways, WAT a necessary step in insulin secretion by increasing the production of reactive can influence the function of many by β-cells. The researchers also oxygen species and inducing apoptosis tissues, such as hypothalamus, pan- detected a decrease in the glucose in the cells (Dembele et al. 2009). creas, skeletal muscle, and immune transporter Glut2 in β-cells as well All of these studies clearly show system. In addition, WAT can as a decrease in insulin synthesis, that heavy alcohol consumption coordinate numerous important further exacerbating the effects of has deleterious effects on pancreatic biological processes through its chronic alcohol exposure. β-cell function and glucose homeo- various adipokines, such as food More recently, Wang and colleagues stasis. However, more studies are intake and body weight (leptin), (2014) reported that intraperitoneal needed to specify the mechanisms glucose homeostasis ( and administration of ethanol (3g/kg by which chronic alcohol affects ), lipid metabolism, pro- and anti-inflammatory functions (tumor body weight) to mice resulted in β-cell function. necrosis factor alpha [TNFα] and an impaired glucose metabolism, interleukin-6 [IL-6]), as well as which was associated with decreased reproductive functions (Campfield expression of two subunits (i.e., Endocrine Adipose Tissue α δ et al. 1996; Coelho et al. 2013). 1 and -subunits) of the type A There are two types of adipose tissue— BAT, on the other hand, is pres- gamma-aminobutyric acid (GABA) white adipose tissue (WAT) and ent at birth but is almost absent in brown adipose tissue (BAT)—that adult mammals. Brown adipocytes 2 Incretin is a hormone secreted by the wall of the intestine that acts on the pancreas to regulate insulin production differ in their morphology and func- are smaller than white adipocytes, after glucose administration. This so-called enteroinsular tion. For a long time, WAT had been have numerous mitochondria, signaling pathway can therefore only occur after oral glucose considered a passive reservoir for and specialize in heat production administration, which results in increased glucose levels in the intestine, but not after intravenous administration, which energy storage. Over the last decade, through oxidation of fatty acids (i.e., bypasses the intestine. however, numerous studies have thermogenesis). However, recent

Pathophysiology of the Effects of Alcohol Abuse on the Endocrine System | e-15 Alcohol and Other Endocrine Tissues (continued)

direct and indirect evidence also frequency of alcohol administration. tor influencing adiponectin secretion suggests a potential endocrine role In a study comparing the effects of and, consequently, insulin sensitivity. for BAT (Villarroya et al. 2013). exposure of high-fat–fed rats to 5 g/kg One proposed mechanism for Thus, BAT was shown to release body weight ethanol per day deliv- the adiponectin-mediated improve- factors such as IGF-1, fibroblast ered either by twice-daily administra- ment in insulin sensitivity is that growth factor-2, IL-1α, IL-6, bone tion via a gastric tube or through the increase in adiponectin causes a morphogenetic protein-8b, and free-access drinking, Feng and col- decrease in plasma levels of TNFα lipocalin prostaglandin D synthase leagues (2012) demonstrated greater (Ouchi et al. 2000; Yokota et al. that primarily have autocrine or improvement of insulin sensitivity 2000). Conversely, decreasing adi- paracrine actions (Villarroya et al. with twice-daily ethanol administra- ponectin levels would be expected 2013). The only known endocrine tion. Accordingly, adiponectin to result in increasing TNFα levels. factor released by BAT is the active plasma levels were significantly High circulating TNFα levels, in thyroid hormone T3. Upon ther- increased in the twice-daily adminis- turn, have been implicated in the mogenic activation, the type II thy- tration group compared with the development of peripheral insulin roxine 5′-deiodinase enzyme, which free-access group. The researchers sug- resistance (Hotamisligil et al. 1995). is expressed specifically in BAT, gested that ethanol concentrations in Chronic alcohol consumption can converts T4 into T3 (de Jesus et the blood might be an important fac- significantly decrease adiponectin al. 2001).

Chronic alcohol Alcohol’s Effects on Endocrine exposure Adipose Tissue Although the results have not been consistent, numerous studies have Liver AT shown that alcohol consumption can change adipokine levels. For exam- ple, studies found that leptin levels - Fat synthesis Leptin were increased (Nicolas et al. 2001; - Adiponectin - Fat degradation Obradovic and Meadows 2002), - TNFα, IL-6 decreased (Calissendorff et al. 2004), - Liver steatosis IGF-1 or remained unchanged (Beulens et - Insulin resistance - Bone marrow - Macrophage al. 2008; Strbak et al. 1998) by alco- density infiltration hol exposure. Another adipokine is - Bone marrow adiponectin, which is produced and adiposity secreted exclusively by WAT and has - Osteoblast antidiabetogenic and anti-inflamma- proliferation tory effects. Its production and - Osteoporosis actions are regulated by TNFα, with the two compounds suppressing each Alcohol and the endocrine white adipose tissue (WAT). WAT is a dynamically active endocrine other’s production and antagonizing organ that produces and secretes adipokines, including hormones, growth factors, and cytokines. each other’s actions in target tissues These factors, through autocrine, paracrine, and endocrine actions, can influence the function (Maeda et al. 2002). Moderate alcohol of many tissues and coordinate numerous important biological processes such as food intake, consumption can increase adiponec- glucose homeostasis, lipid metabolism, and pro- and anti-inflammatory functions. Acute and tin plasma levels, which is associated moderate alcohol exposure induces an increase in circulating adiponectin levels, which is associated with decreased insulin resistance. Chronic alcohol exposure induces a decrease with a significant increase in insulin in adiponectin, an increase in macrophage infiltration and proinflammatory cytokine secretion sensitivity (Sierksma et al. 2004; (e.g., tumor necrosis factor alpha (TNFα) and interleukin-6 [IL-6]) and insulin resistance. Thamer et al. 2004); the extent of Chronic alcohol exposure also increases the risk of fatty liver (i.e., steatosis). this effect, however, depends on the

e-16 | Vol. 38, No. 2 Alcohol Research: Current Reviews Alcohol and Other Endocrine Tissues (continued) levels (Xu et al. 2003).3 Thus, male lower leptin levels than did control Calissendorff, J.; Brismar, K., and Rojdmark, S. Is decreased leptin secretion after alcohol ingestion rats that had received ethanol for 4 subjects, whereas there were no sig- catecholamine-mediated? Alcohol and Alcoholism weeks exhibited significantly decreased nificant differences in leptin concen- 39(4):281–286, 2004. PMID: 15208157 mRNA levels of adiponectin and ret- trations in males with and without Campfield, L.A.; Smith, F.J.; and Burn, P. The OB protein inol binding protein 4 but increased ALD. Gender-related differences (leptin) pathway—a link between adipose tissue mRNA levels of monocyte chemo- in serum leptin concentrations may mass and central neural networks. Hormone and attractant protein 1, TNFα, and influence the clinical course of Metabolic Research 28(12):619–632, 1996. PMID: 9013731 IL-6 in epididymal adipose tissue. ALD, which differs in males and These changes were associated with females. It is possible that metabolic Coelho, M.; Oliveira, T.; and Fernandes, R. Biochemistry increased macrophage infiltration of adipose tissue: An endocrine organ. Archives of alterations caused by ethanol in the Medical Science 9(2):191–200, 2013. PMID: 23671428 into adipose tissue and the devel- course of ALD, by differentially opment of insulin resistance (see Conigrave, K.M.; Hu, B.F.; Camargo, C.A., Jr.; et al. A modulating leptin secretion, may be prospective study of drinking patterns in relation to figure) (Kang et al. 2007). responsible for different clinical pre- risk of type 2 diabetes among men. Diabetes 50(10): In addition, studies have suggested sentations of the disease in females 2390–2395, 2001. PMID: 11574424 that reduced adiponectin expression and males (Kasztelan-Szczerbinska et De Jesus, L.A.; Carvalho, S.D.; Ribeiro, M.O.; et al. The could play an important role in the al. 2013). However, more studies are type 2 iodothyronine deiodinase is essential for development of alcohol-induced needed to help with our understand- adaptive thermogenesis in brown adipose tissue. liver damage (Xu et al. 2003). Journal of Clinical Investigation 108(9):1379–1385, ing of the adipose tissue pathology 2001. PMID: 11696583 Alcoholic fatty liver (i.e., steatosis) associated with alcohol abuse. is one of the most prevalent forms de Menezes, R.F.; Bergmann, A.; and Thuler, L.C. of chronic liver diseases caused by Alcohol consumption and risk of cancer: A systematic literature review. Asian Pacific Journal of Cancer alcohol abuse; it is characterized by References Prevention 14(9):4965–4972, 2013. PMID: 24175760 the excessive accumulation of fat in Dembele, K.; Nguyen, K.H.; Hernandez, T.A.; and Apte, M.V.; Wilson, J.S.; and Korsten, M.A. Alcohol-related the liver and can progress to more Nyomba, B.L. 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PMID: 18191055 Nutrition and Metabolic Care 15(5):457–467, 2012. (Kasztelan-Szczerbinska et al. 2013). PMID: 22797570 The analyses found elevated total Beulens, J.W.; de Zoete, E.C.; Kok, F.J.; et al. Effect of moderate alcohol consumption on adipokines and Hodge, A.M.; Dowse, G.K.; Collins, V.R.; and Zimmet, P.Z. levels of adiponectin and resistin in insulin sensitivity in lean and overweight men: A diet Abnormal glucose tolerance and alcohol consumption in patients with alcoholic liver disease intervention study. European Journal of Clinical three populations at high risk of non-insulin-dependent (ALD) compared with control sub- Nutrition 62(9):1098–1105, 2008. PMID: 17554246 diabetes mellitus. American Journal of Epidemiology 137(2):178–189, 1993. PMID: 8452122 jects. Also, women with ALD had Bonnet, F.; Disse, E.; Laville, M.; et al. 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Pathophysiology of the Effects of Alcohol Abuse on the Endocrine System | e-17 Alcohol and Other Endocrine Tissues (continued)

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Diet-induced insulin resistance in mice lacking adiponectin/ Thamer, C.; Haap, M.; Fritsche, A.; et al. Relationship Zhang, Y.; Proenca, R.; Maffei, M.; et al. Positional cloning ACRP30. Nature Medicine 8(7):731–737, 2002. PMID: between moderate alcohol consumption and adiponectin of the mouse obese gene and its human homologue. 12068289 and insulin sensitivity in a large heterogeneous Nature 372(6505):425–432, 1994. PMID: 7984236 secretion as well as between sleep dis- of chronic alcohol exposure, rats receiving affects GH secretion primarily at the turbances and decreased GH secretion 5 percent ethanol in a liquid diet for hypothalamic level where it induces (Van Cauter et al. 2004). Alcohol- 4.5 months showed a significant decrease impairments in GHRH gene expres- dependent individuals have been shown in circulating IGF-1 levels (Sonntag sion. However, the responsiveness of to have lower levels of slow-wave sleep and Boyd 1988). Similarly, chronic the anterior pituitary to a GHRH power that was associated with lower lev- 6-day administration of 5 percent eth- challenge was the same in both saline- els of GH release compared with normal anol to awake rats resulted in a 75 to and ethanol-injected animals (Dees et control subjects (Lands 1999). 90 percent decrease in spontaneous al. 1988). Similar findings have been obtained GH secretion (Soszynski and Frohman As mentioned earlier, the GH/ in animal studies. In a rat model of 1992). In addition, ethanol treatment IGF-1 pathway regulates carbohydrate binge ethanol exposure, intraperitoneal was associated with significant declines and lipid metabolism. Recent studies injection of one dose of ethanol in IGF-I serum levels and GHRH have suggested that alcohol-induced resulted in a significant decline of GH mRNA levels, whereas somatostatin changes in the circulating levels of serum levels at 0.5, 1.5, and 3 hours or GH mRNA levels did not change IGF-1 and GH might contribute to compared with saline-injected control (Soszynski and Frohman 1992). These the alcohol-mediated development of rats (Emanuele et al. 1992). In a model results suggest that chronic ethanol glucose intolerance and type 2 diabetes. e-18 | Vol. 38, No. 2 Alcohol Research: Current Reviews Glossary

Anabolic: Pertaining to the metabolic processes by Glycogen: A large, highly branched molecule consisting which organisms convert substances into other compo- of chains of glucose molecules; constitutes the major nents the body needs. carbohydrate reserve of animals and is stored primarily in liver and muscle. Apoptosis: Specific pattern of reactions resulting in the death of single cells; also referred to as programmed Insulin Resistance: Impairment of the normal physio- cell death. logical response to insulin that may be the result of a variety of abnormalities; occurs in diabetes mellitus. Autocrine: A mode of hormone action in which a hor- mone binds to receptors on, and affects the functions of, Paracrine: A mode of hormone action in which a hormone the cell type that produced it. binds to receptors on, and affects the functions of, nearby cells of a different type from the cell type that produced it. Autonomic Nervous System: Part of the nervous system Parasympathetic Nervous System that connects the central nervous system to the organs : Part of the autonomic and controls involuntary bodily functions, such as respi- nervous system that operates to help the body conserve energy and resources in a relaxed state. ration and digestion. Promoter C-peptide : Segment of DNA usually in front of a gene : Part of the precursor molecule of insulin that acts as a controlling element in the expression of that gets excised during the final processing of the that gene. insulin molecule; has no physiologic activity. Reactive Oxygen Species: Biologically active, partially Epididymal: Pertaining to the epididymis—the elongated, reduced derivatives of molecular oxygen that are cordlike structure along the rear of the testis that provides produced by normal metabolic processes and which for storage, transit, and maturation of sperm. can damage the cells or their components. Epigenetic: Altering the activity of genes without changing Sympathetic Nervous System: Part of the autonomic their DNA sequences (e.g., through chemical modifica- nervous system that stimulates organs and blood vessels tion of the DNA or the histone proteins around which to help the body react to stressful situations. the DNA is coiled). Total Integrated Response: A measure of the area under Fecundability: The probability that a woman becomes the curve of the insulin or glucose response to an oral pregnant in a certain period of time. glucose challenge used to determine insulin resistance.

In a rat model of type 2 diabetes (i.e., where they release their hormones. the brain, and accumulating evidence the type-2 diabetic Otsuka Long-Evans AVP can be produced by two types suggests it plays an important role in Tokushima Fatty rat model), alcohol of cells (i.e., magnocellular and parvo- social behavior, sexual motivation and administration significantly decreased cellular cells). Magnocellular neurose- pair bonding, and maternal responses IGF-1 serum levels and increased GH cretory cells produce the AVP that is to stress (Insel 2010). In the context of serum levels compared with nondiabetic found in peripheral blood. This AVP is chronic alcohol use, AVP is involved control rats (Kim et al. 2013). These secreted in response to osmotic stimuli in the disturbed water balance observed effects on IGF-1 and GH might con- and is involved in regulating the con- in actively drinking people with AUD tribute to the alcohol-mediated exacer- centration of dissolved molecules and during acute withdrawal (Döring bation of type 2 diabetes in the rats. (i.e., osmolality) in the body fluids by et al. 2003; Ehrenreich et al. 1997). retaining water in the body and con- AVP also may affect cognitive func- stricting blood vessels (Iovino et al. tion, because treatment of alcoholic Alcohol and the HPP Axis 2012; Verbalis 1993). In contrast, AVP patients with memory deficits by using produced by the parvocellular system AVP analogs resulted in improved The HPP axis includes two neuropep- is secreted following psychological cognitive performance (Laczi 1987). tides—AVP and oxytocin—both of stress and is involved in potentiating Finally, studies in rodents have sug- which are produced by cells whose cell the action of CRF on ACTH release gested that AVP may play a role in bodies are located in the hypothalamus (Romero and Sapolsky 1996). Some the development and maintenance but that extend to the posterior pituitary, AVP also may be released directly into of alcohol tolerance (Hoffman 1994).

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