Summary by Nicole Guanci, MD, and Rashi Aggarwal, MD
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Based on “Principles of Addiction Medicine” Chapter by Alan Ona Malabanan, MD, FACE
The effects of alcohol and other drugs on the endocrine system are complex. These substances have an effect on the hypothalamus, thyroid, adrenal glands, pancreas, and other target organs and on metabolism/protein binding. Effects are modulated by multiple factors, including gender, mental illness, specific drugs used, and chronicity of use, making the net effect heterogeneous (Table 82-1).
TABLE 82-1. ENDOCRINE ABNORMALITIES AND RESULTANT SYNDROMES ASSOCIATED WITH ALCOHOL AND OTHER DRUG USE
DISORDERS RELATED TO ALCOHOL
Hypoglycemia/Hyperglycemia
Alcohol causes hypoglycemia by producing malnutrition, reducing gluconeogenesis, and impairing the body’s response to hypoglycemia. Chronic alcohol use has been associated with pancreatitis, pancreatic insufficiency, and the development of diabetes mellitus. However, a U-shaped relationship has been suggested regarding alcohol use and insulin sensitivity risk, with low-to-moderate usage being protective.
Reproductive Consequences
In men, alcohol use can cause sexual dysfunction and hypogonadism, especially when alcoholic cirrhosis is comorbid. In women, effects depend on menopausal status and hormone therapy use. During high-estrogen states, acute alcohol consumption leads to increases in estradiol, resulting in increased breast cancer risk and delay in menopause. Women with high or frequent alcohol intake were found to have higher rates of menstrual disorders, including amenorrhea, dysmenorrhea, and irregular periods. High alcohol intake during pregnancy is associated with a higher incidence of miscarriages, placental abruption, preterm deliveries, and stillbirths. An increased infertility risk, increased prolactin, and decreased oxytocin have been observed in lactating and premenopausal women.
Bone Health Consequences
Chronic alcoholism is associated with decreased bone mass and increased fracture risk. The opposite is true with moderate use.
Other Endocrinologic Consequences
Alcohol use increases triglyceride synthesis, leading to hypertriglyceridemia and hepatic steatosis. Alcohol increases the high-density lipoprotein (HDL) fraction of cholesterol, which may reduce cardiovascular morbidity and mortality.
The glucocorticoid response to hypoglycemia can potentially be impaired by alcohol use. Alcohol may decrease leptin and affect feeding behavior. Alcohol use decreases vasopressin release, leading to water diuresis and increased blood pressure, through increased norepinephrine. Alcohol suppresses melatonin through increased norepinephrine levels, which may cause disturbances in sleep and performance.
TOBACCO
Thyroid Disease
Cigarette smoking increases the risk of Graves disease and Graves ophthalmopathy and can lower thyroid-stimulating hormone levels.
Insulin Resistance and Dyslipidemia
Cigarette smoking is associated with increased insulin resistance, impaired glucose tolerance, and diabetes mellitus, which may in turn increase the risk for cardiovascular and atherosclerotic disease. Mild decreases in HDL cholesterol and mild elevations in triglycerides have been observed.
Reproductive Function
In women, cigarette smoking is associated with decreased estrogen levels, enhanced estrogen degradation, early menopause, increased ovarian age, increased follicular-stimulating hormone (FSH) levels, significantly lower odds of clinical pregnancy per cycle, higher odds of spontaneous miscarriage, higher odds of ectopic pregnancy, and poorer outcomes with assisted reproduction. In men, cigarette smoking is associated with quantitative and qualitative decrements in sperm and increases in serum estrogen.
Bone Health
Cigarette smoking is associated with decreased bone mineral density, femoral head osteonecrosis, and increased bone loss in postmenopausal women. It is an independent risk factor for osteoporotic fracture.
Other Endocrinologic Effects
Cigarette smoke stimulates antidiuretic hormone (ADH) release from the pituitary, which may cause or exacerbate hyponatremia in susceptible patients. Nicotine can increase the release of catelcholamines, adrenocorticotropic hormone (ACTH), and cortisol. Smoking is associated with hypertension and poorly controlled hypertension, through stimulation of the noradrenergic nervous system. Cigarettes also may increase prolactin secretion.
DISORDERS RELATED TO OTHER DRUGS
Marijuana
Heavy marijuana use cause significant hypoadrenalism or impaired recovery from insulin-induced hypoglycemia, in those with preexisting adrenal disease. Otherwise, marijuana increases appetite via interactions with cannabinoid receptors. It is unlikely that chronic marijuana use affects the reproductive system in a clinically significant manner. Marijuana has not been found to be teratogenic.
Opioids
Acute use of opioids primarily affects the endocrine system at the level of the hypothalamus and pituitary. Follicular-stimulating hormone (FSH) and luteinizing hormone (LH) are suppressed by inhibition of gonadotropin-releasing hormone (GnRH) secretion, prolactin secretion is stimulated, and ACTH and cortisol secretion are suppressed. In men, the effects on gonadal function are not consistent. In women, menstrual irregularities have been reported, with impaired gonadotropin release and oligo-ovulation noted. Opioids increase prolactin levels. Opioids have been associated with hypoadrenalism and inhibit the ACTH response to corticotropin-releasing hormone (CRH). There is a potential decrease in bone density and resultant increased fracture risk in both men and women. High-dose opioids may induce growth hormone release and stimulate thyroid-stimulating hormone (TSH) release.
Cocaine
Cocaine blocks the reuptake of norepinephrine, dopamine, and serotonin at synaptic junctions. It stimulates the adrenal medulla to release epinephrine and norepinephrine. By increasing catecholamines, hyperglycemia can result, as can diabetic ketoacidosis or hyperosmolar nonketotic hyperglycemia in the absence of precipitants. Acute cocaine use suppresses prolactin secretion, but the opposite occurs chronically. Although acute cocaine use increases ACTH, FSH, and LH, clinically significant results have not been noted.
Amphetamines
Well-described acute endocrine effects of amphetamine administration include increased corticosteroid release and increased growth hormone release.
Both cocaine and amphetamine have well-known effects on appetite suppression via up-regulation of cocaine- and amphetamine- regulated transcript, interacting with neuropeptide Y, leptin, and cannabinoid (CB1) receptors.
Caffeine
Caffeine causes increased blood pressure via epinephrine release from the adrenal medulla. Caffeine may have acute effects on glucose metabolism. Acute ingestion of 250 mg of caffeine produces an increase in epinephrine, norepinephrine, cortisol, and growth hormone response to hypoglycemia in normal adults and those with insulin-dependent diabetics. Chronic consumption is associated with a decreased risk of type 2 diabetes mellitus. Coffee impairs the intestinal absorption of L-thyroxine and may alter the management of hypothyroidism. The results of caffeine on bone health are inconclusive.
Benzodiazepines
Benzodiazepines suppress basal serum levels of cortisol and the body’s cortisol and ACTH response to insulin-induced hypoglycemia, corticotrophin-releasing hormone, metabolic stress, and exercise. Such changes potentially lead to a hypoadrenal crisis or prolonged hypoglycemia in users with preexisting adrenal disease. This may not apply to all benzodiazepines.
Barbiturates
Barbiturates are known to induce the cytochrome P450 enzyme system, leading to enhanced metabolism of thyroid hormone, hydrocortisone, vitamin D, and methadone. Barbiturate use can lead to increasing thyroid hormone requirements, hydrocortisone requirements, osteomalacia, or opioid withdrawal.
Inhalants
No specific endocrine consequences have been described with inhalant use though occupational exposure to inhalants is associated with infertility, increased risk of spontaneous abortion, and multiple birth defects.
Anabolic Steroids
The endocrine system is affected by anabolic steroids due to their androgenic effects and suppression of the hypothalamic–pituitary–gonadal axis. Anabolic steroids thus cause testicular atrophy; decreased testosterone, LH, and FSH; increased estrone; gynecomastia; and suppression of spermatogenesis with resultant infertility. In women, menstrual disturbances, deepening of voice, acne, and male pattern body hair are possible. Anabolic steroids can affect other hormones by decreasing hepatic synthesis of proteins, such as thyroid-binding globulin, sex hormone–binding globulin, vitamin D–binding protein, and HDL cholesterol. Clinically relevant sequelae are not present without underlying pathology. Growth hormone levels can rise and cause hypogonadotropic hypogonadism. No significant changes in bone metabolism have been noted in adults.
Other Drugs
No endocrinologic consequence has been described with phencyclidine or lysergic acid diethylamide (LSD) use. Further research is required on these drugs.
KEY POINTS
1. Alcohol and other substances have an effect on multiple organ systems, modulated by multiple factors and creating a heterogeneous net effect on the endocrine system.
2. Alcohol is associated with diabetes insipidus, gynecomastia, hyperadrenalism, hyperglycemia, hypoglycemia, hyperlipidemia, possible hyperprolactinemia, hypogonadism/infertility, hypertension, and osteoporosis.
3. Tobacco is associated with hyperlipidemia, hypogonadism/infertility, hypertension, hyperthyroidism, possible hypothyroidism, osteoporosis, and SIADH.
REVIEW QUESTIONS
1. Which of the following has NOT been associated with chronic alcohol use?
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