Relationship between Substance use and Endocrine Disorders: A Narrative Review

Substance use disorder is one of the signiﬁcant public health concerns and the co-morbidity with endocrine disorders has a poten�al to cause adverse outcomes. There is a deﬁnite link between substance use and dysregula�on of endocrine system at a level of causa�on, associa�on, management and drug interac�on. It has been seen that the screening of substance use while managing endocrine disorders is a must. Also, integrated management of both of these chronic condi�on with collabora�ve care approach can not only help in eﬀec�ve management but also improve the outcomes in terms of mortality, cost eﬀec�veness, s�gma and ﬁnancial burden. Though considered important this common area seems to be understudied. Hence we recommend that this co-occurrence of substance use and endocrine disorders should be studied and guidelines be developed for the eﬀec�ve management.


INTRODUCTION
Psychoac ve substance (substance) use as a risk factor accounts for 11% of total health burden globally and is 1 regarded as a major public health concern.United Na ons' Sustainable Development Goals for 2030 has featured preven on and treatment of substance use disorders (SUDs) in the targets highligh ng the need to focus on these 1 addic ve disorders.Substance use disorders pose addi onal challenges due to their intricate associa on with other medical disorders.Endocrine disorders are among such disorders that share a mul faceted interface with substance use disorders.A review from US states that the prevalence es mates of endocrine disorders even without co-morbidity have posed a 3 significant public health burdens.The co-occurrence of these condi ons adds to the burden.Substance use disorder can present as co-morbid condi on along with different endocrine disorders and also serve as a risk factor for 4 emergence of endocrine disorders.Substance use disorders can complicate the clinical presenta on, diagnosis, management, course and outcome of the endocrine disorders when the two occur as comorbidity.More importantly, this interac on is not unidirec onal and even the endocrine disorders impact the emergence, management, course and outcome of the substance use disorders in different ways.There is much higher expenditure for the pa ents who have comorbid substance use disorder and medical disorders like endocrine disorders due to hospitaliza on, prescrip on drugs, clinical visits than those 5 without such comorbidi es.Also lack of screening services and integrated care tends to delay the management and impact the course and outcome adversely.This shortcoming of the clinical care delivery is partly a ributable to limited

Relationship between Substance use and Endocrine Disorders: A Narrative Review
focus on this comorbidity in research studies For instance substance use in type 2 diabetes has been described as 6 'dangerous but understudied' problem.It has been highlighted that SUDs in persons with complex healthcare needs, especially endocrine disorders are insufficiently studied and need systema c explora on to inform targeted 7 screening and care-coordina ng efforts.In this ar cle we aim to provide a narra ve overview of the co-morbidity of these two set of disorders and offer recommenda ons on assessment and management of the same.We also highlight the research need in this area going ahead.

Substance use as risk factor for endocrine disorder
Psychoac ve substance use has been iden fied as a risk factor for emergence of certain endocrine disorders.Exogenous opioids when consumed as substance of abuse have effects on mul ple levels of the endocrine system, although the mechanisms are not yet fully elucidated.There have been reports of chronic opioid use being implicated in 8 adrenal sufficiency.There is ample evidence that chronic opioid use can cause hypogonadotropic hypogonadism in both men and women.Although less frequent, cor sol deficiency can also be found among those with chronic opioid use.The data on the impact of opioids on GH and TSH are not much clear.Hyperprolac naemia can be occasionally detected along with opioid use disorder.One of the important nega ve impacts mostly overlooked of opioids on 9 endocrinology is the bone health.Opioid administra on leads to a metabolic state similar to diabetes and it can also worsen diabetes by decreasing insulin secre on in both humans and animal models.There is a role of opioids in glucose hemostasis and exogenous opioids might lead to 10 higher chances of individuals having diabetes.Alcohol use is one of the important cause of pseudo-11 Cushing's syndrome.The associa on between both acute and chronic alcohol consump on and lower testosterone 11 levels have been demonstrated in research studies.In a study comparing 66 men with alcohol use disorder with 30 controls without alcohol use disorder it was found that chronic alcohol consump on significantly increased FSH, LH, 12 and estrogen levels.This could lead to the symptoms of hypogonadism hypoac ve sexual desire, erec le dysfunc on, and reduced sperm quality and quan ty in men.In case of female too the alcohol can cause the symptoms of hypomenorrhea, amenorrhea, and other menstrual irregulari es due to the altera on of the hormonal levels.One of the mechanisms for hypogonadism due to alcohol use is via alcoholic liver disease, but it can also cause hypogonadism independently in the absence of severe liver disease.In addi on, the people with alcohol dependence o en show dysregula on of the hypothalamic-pituitarythyroid axis.A study showed a significant reduc on in T4 and T3 concentra ons in the chronic alcohol using groups during withdrawal and early abs nence, compared to non-alcohol 13 taking healthy groups.Also there has been evidence of a blunted response of TSH to TRH in persons with alcohol use disorder during early withdrawal.This was found to be posi vely correlated with severity of withdrawal symptoms.However, a er longer periods of abs nence, thyroid dysfunc on was found to recover and thyroid hormones and 14 TSH response to TRH returned to normal levels.This, in turn, causes hormonal disturbances that leads to various disorders such as stress abnormali es, reproduc ve deficits, body growth defect, thyroid problems, immune dysfunc on, cancers, bone disease and psychological and behavioral [15][16] disorders.
One of the most important areas is the rela onship between alcohol use and diabetes.Some evidence suggest that alcohol consump on reduces the incidence of type 2 diabetes mellitus especially in women and non-Asian popula ons whereas binge drinking seems to [17][18] increase the incidence..In a study with 4536 par cipants in China higher alcohol intake appeared to be causally associated with increased risk of diabetes, even for moderate alcohol use It has been seen that alcohol antagonizes the 19 .insulin-s mulated glucose disposal in peripheral ssues and suppress the hepa c glucose produc on via alcohol induced damage or alcohol induced liver disease.Also, chronic alcohol use leads to pancrea c ꞵ-cell dysfunc on and apoptosis which may then lead to diabetes.2021 Smoking has been iden fied as a risk factor for Graves' disease and Graves ophthalmopathy.Moreover, this risk is 22 reduced on tobacco cessa on.Another important effect of smoking is osteoporosis via its effects on various hormones especially an -estrogenic effect in women.Smoking might also cause fer lity problems and premature menopause.'23Smoking causes changes in insulin secre on by the β cell of the pancreas and can mediate insulin resistance.This results in impaired glucose metabolism that can lead to development of diabetes.Also, smoking-induced endothelial dysfunc on has a key role in the development of vascular complica ons 24 of diabetes.A meta-analysis of 22 eligible ar cles represen ng 343,573 subjects and 16,383 pa ents with type 2 DM from Japan es mated that 18.8% of DM cases in men and 5.4% of DM cases in women were a ributable to 25 smoking.Maternal smoking and even passive smoking can delay growth of young children through decrease in Growth 26 Hormone.Cannabis use can lead to subtle lowering of T4 hormone, decrease in testosterone, oligospermia and impotency in male, and inhibit the secre on of growth hormone especially impac ng the fetal growth.Overall cannabis has a depressant effect on most of the hormones but their clinical [27][28] implica ons are yet to be revealed clearly.The impact of use of substances like cocaine and inhalants on endocrine system are less studied.There are several effects of the short-and long-term of inhalant abuse mainly in energy and metabolic processes and glycemic control.It can cause dysfunc on of metabolic homeostasis through altered adipose ssue, bone, and hypothalamic-pituitary-adrenal 29 axis func on.Several hormonal effects are seen in cocaine abuse like disrup on of HPA axis and gonadal axis hormones and need for further studies is highlighted to see the clinical in the endocrine effects of Amphetamine-type s mulants (ATS), however3, 4-Methylenedioxymethamphetamine (MDMA) has been shown to increase plasma concentra ons of cor sol, prolac n, and oxytocin compared with placebo.There are case reports of ATS leading to dysregula on of blood glucose level in diabetes which needs further [32][33] research.What makes it even more challenging clinically is the fact that the endocrine manifesta ons of substance use and SUDs are probably more o en subclinical than clinically overt.The knowledge about the range and scope of these poten al endocrine effects of substance use and SUDs can make a clinician more vigilant for clinically relevant disturbances whenever they tend to occur.

Endocrine disorders as a risk factor for SUDs
It is seen that endocrine disorder could be a risk factor for substance use.An electronic health record data of 211880 from USA showed that substance use (tobacco, alcohol, any drug) was significantly more prevalent among pa ents with 34 diabetes than those without it (22.5% vs 11.9%) .Another study among 166 adults with type 1 diabetes showed frequencies of substance similar or more that of the general popula on, fairly high misuse of prescrip on opioid and 35 seda ves, and frequent drinking.It is usually seen that youths with chronic medical condi on have a higher tendency to have substance use problems which could be a form of self-medica on for disease symptoms or comorbid 36 depression or anxiety.On the basis of pathophysiological mechanism it is seen that any event that leads to change in HPA ac vity like stress leads the pa ent with substance use 37 disorder to relapse.The onset and con nua on of an endocrine disorder is stressful for the pa ent.It has been seen that situa ons causing stress can increase the vulnerability to substance use disorder both in terms of development of dependence and risk of relapse.The psychological theories view substance use as a coping strategy to deal with stress or reduce tension.The neurological theories explain this in terms of involvement of the mesolimbic dopamine, glutamate, and gamma-amino-38 butyric acid (GABA) pathways.One of the neurobiological hypothesis states that in pa ents with diabetes the disrup on in insulin signaling causes suppression in the dopamine system.This can enhance substance reward and thus explain higher prevalence of substance like nico ne in diabetes.

Impact of Substance use on management of endocrine disorder
When we look at diabetes as a prototype endocrine disorder it can be seen that the pa ents who have comorbid substance use disorder present with more adverse outcomes and poorer adherence to diabetes care than those without a 40 substance use disorder.A randomized controlled trial showed that diabetes could significantly increase the likelihood of premature death among people with cooccurring substance use disorders at the end of 12 years (41% 41 with diabetes compared to 10% without diabetes).Apart from that there are many consequences of untreated substance use disorders on the medical complica ons of diabetes as well.The substance use might also hamper the implementa on and comple on of structured educa on which is underpinning component of successful management 42 of Type 2 DM.When we look at the financial burden, a study done from the Veteran Health Administra on and Medicare fee-for-service claims database (fiscal years 1999 and 2000) with sample size of 390,253 showed that the total average expenditure was highest among the pa ent who had comorbid diabetes and substance use as compared to only 43 diabetes group.There are many substances that may interact with the drugs given for endocrine disorders.For example sulfonylureas used in the treatment of diabetes has an interac on with alcohol where alcohol inhibits hepa c gluconeogenesis and increases the risk of developing hypoglycemia during sulfonylureas treatment and even may 44 cause disulfiram-like flushing reac on.Both endocrine disorders and substance use involve a wide range of neurotransmi ers, hormones, and different other biological systems, the treatment of one can influence the other which are yet to be delineated.Some of the examples are men oned in Table 1.

Screening and integrated management:
Like most of the endocrine disorders, substance use disorder is also a chronic condi on that needs to be monitored and managed clinically over a long period of me in order to reduce the risk of relapse and promote full recovery.In the me where psychosocial aspects of different endocrine disorders are being highlighted in causa on, associa on and 45 management ., the integra on of substance use disorder in the form of screening, brief interven on and referral to specialist can be done along with the treatment of endocrine disorders.Endocrine clinics as well as primary health care centers can present as a unique opportunity in this regards.There are two major models with which we might be able to link the substance use disorders and endocrine disorders.The first model known as centralized model brings primary care, mental health, and/or substance abuse services together at a single site.This is also known as one-stop shopping model that has been implemented in primary care clinics and substance use disorder treatment programs.This model helps to overcome the substan al poli cal, bureaucra c, a tudinal, geographical and financial barriers that separate substance-dependent persons from needed services. 46A randomized controlled trial among 592 adults from a large health maintenance organiza on chemical dependency program in Sacramento, Calif showed that the individuals having substance abuse related medical condi on benefit from integrated medical and substance abuse treatment, and such an approach can be cost-effec ve. 47Another model for linking is a distribu ve model.Here the sites providing care for endocrine disorders can be linked by effec ve systems to refer pa ents with substance use disorder to the specialized site.Successful referral is the core task of the distribu ve model.However, evidence suggest that referral alone cannot integrate the care of pa ents with substance use disorder in primary care se ngs.Collabora ve care model incorpora ng evidence-based integra ve medicine interven ons that includes care coordina on, enhancing inter professional communica on, non-pharmacological interven ons/ complementary therapy and physical integra on of primary and secondary health care have been proposed to adequately address mental health problems with comorbid medical condi ons.Similar approach can be applied in case 48 of coexis ng substance use and endocrine disorders.One direc on in this regards could be u liza on of a chronic care management model which have the standards for pa ent-centered medical homes, the one devised by the Na onal Commi ee for Quality Assurance.These standards provide the criteria for guiding and measuring quality of health care and coordina on, involving team management of chronic diseases among primary and behavioral health care providers.This may be relevant for pa ents with coexis ng substance use disorders and endocrine [49][50] disorders.
These standards are defined across six categories: • Enhancing care access and con nuity of care both of which are important to pa ents with coexis ng disorders such as endocrine and substance use disorder • Collec ng data for iden fying and managing pa ent at popula on level • Planning and managing care using evidence-based guidelines for preven ve, acute, and chronic care (including medica ons) management and iden fying pa ents with high-risk condi ons, such as endocrine disorders or substance abuse problems • Providing self-care support and community resources including assessing and providing treatment for pa ents with substance abuse comorbid with endocrine disorders • U lizing health informa on technology like electronic health records, to track, follow up on, and coordinate medical tests, referrals, and transi ons of care • Evalua ng performance using measures for con nuous quality improvement There is a public health need of integra on of preven ve screening and substance use disorder treatment into community diabetes care or other endocrine disorders.However this area of integra on needs research in different domains to assess the outcomes and cost-effec veness of integrated treatment in terms of durability and performance (e.g.clinical quality measures), implementa on strategies, 51 sustainability, compara ve effec veness.We emphasize that any person newly diagnosed with endocrine disorder or coming to endocrine clinic for followup must be asked about psychoac ve substance use.Detailed evalua on regarding history of psychoac ve substance use mainly dura on, quan ty, frequency, last dose, usual dose should be enquired systema cally.If me permits the diagnosis can be made using The Interna onal Sta s cal Classifica on of Diseases and Related Health Condi ons (ICD)-10 or the Diagnos c and Sta s cal Manual of Mental Disorders-5 but this might not be always prac cal considering the constraints of me and exper se hence simple screening for substance abuse should be made mandatory.There are various screening tools available which are valid and take short me to assess substance use

CONCLUSION
It is a known fact that the incidence of both substance related disorders and endocrine disorders are on a rise.There is a definite associa on between the two at a level of causa on, associa on, management and drug interac on.The endocrine clinics can act as an important place to screen and intervene for substance use disorder for which a collabora ve and integra ve approach is a must.Major clinical treatment guidelines for endocrine disorders and substance use disorders do not address the pa ents who have coexistence of both the condi ons.Hence, it has been deemed necessary to focus in this special co-occurring condi ons.Also, when we make permuta ons and combina ons of different disorders between these two vast areas, we will definitely find different areas of concern and many clinical implica ons.The large popula on-based epidemiological studies in people with both substance use and endocrine disorders are needed.The longitudinal studies should be conducted to be er understand the me course of onset and outcomes of endocrine disorders in rela on to SUDs and randomized controlled trials are needed to assess safety and efficacy of promising psychosocial and pharmacological interven ons for this common area.
30 implica ons..There are very few studies that have looked Review Article J Psychiatrists' Association of Nepal Vol.11, No.1, 2022 Sharma P. et al.Rela onship between Substance use

Box 2 :
52 problems.[Box 1].It is important to iden fy some red flag signs for substance use among the pa ent with endocrine disorder.Regular screening and high index of suspicion based on "red flags" can be done in primary care se ng or endocrine clinic.[Box 2].It should be noted that the presence even one sign should raise suspicion but none of the red flags is pathognomonic for 53 , substance use.Box 1: Screening tools • WHO-ASSIST • CAGE ques onnaire • Alcohol Use Disorders Iden fica on Test (AUDIT) • Fagerström Test for Nico ne Dependence (FTND) • Opioid Risk Tool • Drug Abuse Screening Test (DAST) Red flag signs for substance use in endocrine disorders • Problems in Sleep • Pa ents with comorbid mental disorder and self-harm • Signs of chronic obstruc ve pulmonary disease, hepa s B or C, HIV infec on • Any physical finding not consistent with the endocrine disorder • Any lab parameters that is not consistent with the endocrine disorder • Atypical feature of endocrine disorder • Endocrine disorder failing to respond in the expected manner to treatment • History of rela onship difficul es, poorly explained trauma etc

Table 1 :
Review Article J Psychiatrists' Association of Nepal Vol.11, No.1, 2022 Sharma P. et al.Rela onship between Substance use Interac on between drugs used in endocrine and substance use disorder