drink per day (Kato et al. 1989; Nasca et al. 1990; Willet et al. 1987), other investigators have not found compelling evidence to support this finding (Chu 1989). Alcohol has not been implicated in other female cancers, such as endometrial cancer (Webster and Weiss 1989) or uterine or cervical cancer (Licciardone et al. 1989).

Several hypotheses have been advanced to explain the possible carcinogenic effect of alcohol; however, our understanding is far from complete. These hypotheses include the following: 1. By acting as a solvent, alcohol affects the integrity of biological membranes, thereby enhancing the ability of known carcinogens to penetrate the lining of the upper airways (Garro and Lieber 1990; Rothman 1980).

2. By inducing the microsomal P450 enzyme system, which is responsible for the metabolism of known carcinogens and xenobiotics, alcohol may enhance liver capacity to metabolize precarcinogens to toxic metabolites (IngelmanSundberg et al. 1990).

3. Heavy consumers of alcohol may have a decreased intake of dietary factors known to attenuate the risk for certain cancers (vitamins A and E, B-carotene, fiber) (Stemmerman et al. 1990).

4. Alcohol may suppress the body's immune responsiveness, especially by decreasing NK cell activity (Meadows et al. 1989, 1990; Mufti et al. 1989), thereby decreasing the ability to combat tumors.

Alcohol and the Endocrine System

The endocrine system releases chemical mediators called hormones into the circulation to act on other remote tissues. At the level of the hypothalamus and pituitary, there is an intimate link between the nervous and endocrine systems that integrates these two systems into one functional unit. Hormones are involved in such diversified domains as reproduction; growth and development; maintenance of body fluids, electrolytes, and temperature; and regulation of blood pressure and heart rate, to name a few. Alcohol affects not only the synthesis and release of hormones but also their transport, interaction with tissues, and metabolism. The effects of alcohol on various aspects of the endocrine system will be discussed under the following topics: the hypothalamic-pituitary-gonadal (HPG) axis, the

hypothalamic-pituitary-adrenal (HPA) axis, and the hypothalamic-pituitary-thyroid axis (HPT).

The HPG Axis

Reproductive function depends on the precise integration of hormonal signals from the hypothalamus, pituitary, and reproductive organs (ovaries and testes). In this system, referred to as the HPG axis, the hypothalamus secretes a hormone called gonadotropin-releasing hormone (GnRH), which stimulates the pituitary to release two major hormones known as luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These hormones, in turn, control the function of the ovaries and testes.

Alcohol and the male reproductive
system

Numerous studies have clearly demonstrated the adverse effects of alcohol abuse on gonadal function. As early as 1948, hypogonadism (testicular atrophy, impotence, and loss of libido) was clinically recognized in male alcoholic cirrhotic patients (Lloyd and Williams 1948). Later, the effects of alcohol abuse as an independent contributor to disturbances in gonadal function were studied in a healthy population (Van Thiel et al. 1974). In 1976, Gordon et al. reported a decrease in testosterone level in a healthy group of men as early as 5 days after alcohol exposure. Since these initial studies, numerous investigations in animals and humans have confirmed the suppressive effect of alcohol on testosterone levels (Adams and Cicero 1991; Akane et al. 1988; Cicero 1981; Esquifino et al. 1989; Gavaler et al. 1980; Orpana et al. 1990; Widenius et al. 1989). Alcohol-induced decrease in testosterone was attributed to a direct effect on the testes (Mendelson et al. 1977). This direct toxic effect of alcohol on the gonads was recently confirmed by investigators who found that injection of human gonadotropin did not reverse alcohol-induced decrease in testosterone (Adams and Cicero 1991; Orpana et al. 1990).

Several investigators believe that alcohol must be first metabolized to acetaldehyde to produce its toxic effect on the testes (Orpana et al. 1990). This belief is based on the finding that 4methylpyrazole, which blocks the metabolism of alcohol to acetaldehyde, reversed alcohol's effects on the testes. Rivier et al. (1990) suggested that an alcohol-induced increase in corticosterone levels might affect testosterone synthesis or release. Rosenblum et al. (1989) reported that

lipid peroxidation was responsible for alcoholinduced testicular damage.

In addition to its direct effect on the testes, alcohol affects the hypothalamic-pituitary unit. Chronic alcohol exposure was found to decrease serum LH levels in intact (Salonen and Huhtaniemi 1990) and castrated animals (Emanuele et al. 1991). Furthermore, alcohol is thought to block the release of GnRH from the hypothalamus (Chin 1988).

Acute alcohol intoxication did not affect the secretion of gonadotropins or LH. Thus, it was hypothesized that acute alcohol consumption directly impairs testicular function rather than disturbing central regulatory mechanisms. Chronic alcohol abuse, however, involves the hypothalamic-pituitary unit (Valimaki, Pilkonen et al. 1990; Valimaki, Tuominen et al. 1990).

Alcohol and the female reproductive
system

Chronic alcohol abuse in women of childbearing age has been associated with menstrualcycle-related disturbances such as amenorrhea (complete cessation of menses) and anovulation (failure to ovulate) (Seki et al. 1991). Alcoholic women were found to have a higher rate of early menopause (Gaveler 1988) and a higher frequency of menstrual irregularities (duration, flow, or both) (Becker et al. 1989) than nonalcoholic women. In addition, persistent increases in prolactin hormone level in the blood were reported in alcoholic women (Teoh et al. 1992). Alcohol-induced reproductive disorders have been replicated in a primate model for alcoholism (Mello et al. 1988). These disturbances are clinically significant since they lead to impaired fertility either by preventing pregnancy or by increasing the risk for spontaneous abortion. Spontaneous abortion may be explained by the finding that alcohol suppresses the hormone progesterone, which is essential for the maintenance of pregnancy (Teoh et al. 1990). There appears to be a relationship between the amount of alcohol consumed and the severity of these disorders (Mendelson and Mello 1988). Furthermore, alcohol consumption during pregnancy does compromise human fetal development (see Chapter 9, Effects of Alcohol on Fetal and Postnatal Development).

Alcohol-induced endocrine abnormalities in postmenopausal women were first reported by Hugues et al. (1978, 1980). In these women, heavy alcohol consumption was associated with elevated estrogen levels, reduced LH and FSH

levels, and increased prolactin levels in patients with (Becker et al. 1991) or without (Gavaler et al. 1991) liver cirrhosis. The increase in estrogen levels associated with moderate alcohol drinking in postmenopausal women may explain alcohol's apparent protective effects against coronary heart disease (Gavaler et al. 1991).

With the rise in alcohol use among preteens and adolescent youth, it is important that the effect of alcohol use on maturational processes, including growth and sexual maturity, be studied. Alcohol has been reported to delay puberty in animals (Bo et al. 1982). A recent study (Dees 1990) confirmed this finding and demonstrated a significant decline in growth hormone and LH levels during the peripubertal period.

Alcoholic women were found to have a higher rate of early menopause and a higher frequency of menstrual irregularities (duration, flow, or both) than nonalcoholic women.

The HPA Axis

The HPA axis, which comprises the hypothalamus, pituitary, and adrenal glands, is stimulated by alcohol. The hypothalamus secretes a hormone known as corticotropin-releasing factor (CRF), which stimulates the pituitary to release a hormone called adrenocorticotropic hormone (ACTH). ACTH, in turn, stimulates the adrenal gland to secrete hormones (such as corticosterone or cortisol) that affect metabolism and others (such as aldosterone) that affect mineral and fluid balance. Oral administration of alcohol to humans resulted in an increase in plasma corticosteroids (Lukas and Mendelson 1988; Thiagarajan et al. 1989). In alcoholics, the coexistence of liver disease, malnutrition, depression, and other stressors (such as fluctuations between intoxication and withdrawal) influence the net effect of alcohol on the HPA axis. However, the most dramatic alteration in the HPA axis of alcoholics is a condition known as pseudo-Cushing's syndrome, which is characterized by elevated cortisol production, clinical signs and symptoms of hypercortisolism, and resolution of clinical features following abstinence (Wand and Dobs 1991).

The HPT Axis

The hypothalamus secretes a hormone called thyrotropin-releasing hormone (TRH), which acts on the pituitary to stimulate the secretion of thyroid-stimulating hormone (TSH). TSH, in turn, stimulates the thyroid gland to secrete hormones known as T3 and T4. The fact that alcohol consumption decreases serum T4 levels may reflect the influence of liver disease and malnutrition (Loosen 1988). While basal TSH levels are generally normal in alcoholics, a blunted TSH response to TRH (which may persist in alcoholics even several years after becoming abstinent) is the most characteristic abnormality of the HPT axis in alcoholism (Loosen et al. 1990). Several factors, including activation of the HPA axis, may contribute to the impaired TSH response to TRH in alcoholics.

With the advent of new in vivo imaging technologies such as magnetic resonance imaging (MRI), positron emission tomography (PET), and single photon emission computed tomography (SPECT), it is now possible to follow the natural progression in living individuals of neurochemical and structural changes from the early stages of acute intoxication to more chronic alcohol-related neurologic conditions such as the Wernicke-Korsakoff syndrome.

Alcohol-Related Neurologic Disorders

Multiple neurologic effects are associated with acute or chronic alcohol exposure. Adams and Victor (1989) have divided the neurologic consequences of alcohol exposure into the following six categories based on known or suspected etiologic mechanisms: (1) acute alcohol intoxication produced by high alcohol levels; (2) the abstinence or withdrawal syndrome, manifested by tremulousness, hallucinosis, seizures, or delirium tremens; (3) nutritional diseases of the nervous system secondary to alcoholism, such as the Wernicke-Korsakoff syndrome, polyneuropathy, and pellagra; (4) fetal alcohol syndrome (see chapter 9); (5) diseases of uncertain pathogenesis associated with alcoholism, including alcoholic dementia, cerebral atrophy, cerebellar

degeneration, and rarer conditions; and (6) neurologic disorders, such as hepatic encephalopathy, consequent to alcohol-induced liver disease.

Many of these neurologic disorders are characterized by cognitive deficits and structural brain lesions. However, there is often heterogeneity in the presentation of clinical symptoms and poor correlation with location and extent of neuropathological lesions (Harper and Kril 1990; Harper et al. 1986; Jernigan, Butters et al. 1991; Torvik et al. 1982). While varying degrees of alcohol abuse are the common denominator of these neurologic disorders, current research suggests that a combination of etiologic factors, including the direct neurotoxic effect of alcohol and its metabolites, nutritional deficiencies, liver damage, genetic predisposition, and other factors (for instance, educational level, premorbid functioning, alcohol-related head injuries, psychiatric status, age of onset and duration of drinking), may explain individual susceptibility to alcohol-related neurologic disorders (Charnass et al. 1989; Goldstein 1987; Schafer et al. 1991; Sinha et al. 1989).

For example, advances in genetics and molecular biology may help explain why not all malnourished alcoholics go on to develop the Wernicke-Korsakoff syndrome, a disorder characterized by ocular and gait disturbances, confusion, and psychosis. There has been continuing speculation that some inborn defect in the thiamine-dependent enzyme transketolase may bring about a predisposition to thiamine depletion, and variant forms of transketolase have been found in familial chronic alcoholics and Wernicke-Korsakoff patients (Blass and Gibson 1977; Mukherjee et al. 1987; Pratt et al. 1985).

With the advent of new in vivo imaging technologies such as magnetic resonance imaging (MRI), positron emission tomography (PET), and single photon emission computed tomography (SPECT), it is now possible to follow the natural progression in living individuals of neurochemical and structural changes from the early stages of acute intoxication to more chronic alcoholrelated neurologic conditions such as the Wernicke-Korsakoff syndrome. This knowledge could make it possible to prevent and treat severe neurologic disorders through early diagnosis. Furthermore, the potential of PET and SPECT to visualize cholinergic, benzodiazepine, and serotonin receptors in the human brain could make it possible to identify and test more effective pharmacologic agents for the treatment of

alcohol-related neurologic disorders (Jagust 1992; Laruelle et al. 1992).

Acute Neurologic Effects of Alcohol

Mild symptoms of acute alcohol intoxication, such as altered mood, impaired cognition, and incoordination, develop at low blood alcohol concentrations (BACS) (that is, .025 percent). These symptoms have been attributed to neurochemical and electrophysiological disruptions in neuronal pathways (see Chapter 4, Actions of Alcohol on the Brain) in the reticular formation of the brain stem, cerebral cortex, and cerebellum (Klemm 1979). At higher BACS (0.1 percent), additional signs of vestibular and cerebellar dysfunction appear, such as involuntary rapid eye movements, double vision, speech disorders, and lack of muscular coordination. Involvement of the autonomic system may result in hypotension, hypothermia, stupor, coma, and possibly death if excessively high BACs are attained (>0.5 percent) (Charness et al. 1989). Alcoholic blackouts episodes of memory loss that cannot be attributed to global loss of consciousness, seizures, head trauma, or the amnesic disorder Wernicke-Korsakoff syndrome-also result from consumption of large quantities of alcohol (Zucker et al. 1985). All of these acute symptoms may affect individuals with or without alcoholism and in most cases are reversible.

Alcohol's disruptive effects on cognition and motor functioning have direct implications for transportation safety and accidental injury, and dose-related effects of alcohol on perception, psychomotor skills, memory, attention, and information processing have been well documented (Linnoila et al. 1980; Lister et. al. 1987; Morrow et al. 1990; Moskowitz et. al 1985). However, until recently, relatively few experimental studies have measured the effects of acute alcohol administration on oculomotor functions, which could also have significant implications for driving, flying, and operating equipment in the workplace. Several experimental studies have shown that at low to moderate BACS (.03 to .085 percent), impairments are found in vestibulo-ocular reflexes and in the ability of the eye to track a moving target (Katoh 1988; Takahashi et al. 1989). Visual constancy, which refers to the brain's ability to compensate for distorted retinal images and is important for accurately detecting changes in speed, is also affected by low doses of alcohol (Farrimond 1990).

While no specific neuropathologic changes are associated with acute intoxication, regional brain metabolic changes have been demonstrated by noninvasive PET imaging following acute alcohol administration. Recent studies have shown that at low to moderate BACS (.04 to .06 percent), energy metabolism decreased in the cortex and cerebellum (de Wit et al. 1990; Volkow et al. 1990). In vivo autoradiographic studies of glucose metabolism in animals allow visualization of these effects in more discrete subcortical brain areas. Acute alcohol administration produced decreased energy metabolism in brain stem areas of rats, including the vestibular nuclei associated with ocular movements (Eckardt et al. 1988; Porrino 1992). As the technical limitations in imaging techniques are overcome and as sophisticated measures of behavior are developed, it will be possible to study brain activity associated with specific clinical, cognitive, and subjective mood-altering effects of alcohol.

Alcohol Withdrawal Syndrome

Alcohol-dependent individuals who stop drinking or reduce their alcohol intake undergo a withdrawal process that may vary in severity. The most common withdrawal syndrome is mild in nature, occurs within 24 to 36 hours after cessation of drinking, and is characterized by mild agitation, tremor, anxiety, anorexia, restlessness, and insomnia. In a small percentage of cases (less than 5 percent of hospitalized patients in alcohol withdrawal), a more severe reaction develops that involves autonomic, psychomotor, and verbal hyperactivity, auditory or visual hallucinations, and disorientation and confusion (the hallmarks of delirium tremens) (Naranjo and Sellers 1986). Grand mal seizures develop in 5 to 15 percent of alcoholics in withdrawal and occur from 6 to 48 hours after discontinuation of alcohol (Naranjo and Sellers 1986).

Since alcohol withdrawal affects many neurotransmitter and neuroendocrine systems, numerous drugs have been tested to treat it (Nutt and Glue 1990; Wilkins and Gorelick 1986). The most widely accepted pharmacotherapy for withdrawal symptoms is the prophylactic use of benzodiazepines (Charness et al. 1989; Naranjo and Sellers 1986). Propranolol (a B-adrenergic receptor blocker) and clonidine (an a-2-adrenergic receptor agonist), which reduce the overactivity of adrenergic neurons, are used to treat symptoms of severe tremor or cardiac arrhythmias (Charness et al. 1989; Naranjo and Seller 1986). Those

antipsychotic drugs that are less likely to cause sedation or hypotension, or induce seizures, are administered to control hallucinations (Charness et al. 1989; Naranjo and Sellers 1986).

Three categories of organic brain disease associated with chronic alcoholism have been distinguished in the recent literature based on neuropsychological profiles: the Wernicke-Korsakoff syndrome, alcoholic dementia, and "nonamnesic" or "non-Korsakoff" disorders.

Since most drugs have the potential for crosstolerance or toxic side effects, it has been suggested that in very mild cases of withdrawal no pharmacotherapy is needed (Naranjo and Sellers 1986). However, recent studies have shown that, through a process of sensitizing the central nervous system referred to as “kindling" (Ballenger and Post 1978), repeated detoxification may increase the severity of withdrawal symptoms, particularly the incidence of withdrawal seizures (Lechtenberg and Worner 1990; McCown and Breese 1990). Thus, medical treatment of withdrawal symptoms may be warranted to avoid increasing the risk of seizures, and development of new therapeutic agents with minimal adverse effects is under way. For example, in light of findings of the involvement of calcium channels (Brennan et al. 1990) and excitatory neurotransmitter systems such as N-methyl-D-aspartate (NMDA) in alcohol withdrawal (Gulya et al. 1991; Hoffman et al. 1990; see also Chapter 4, Actions of Alcohol on the Brain), calcium channel antagonists (Whittington et al. 1991) and NMDA receptor antagonists (Grant et al. 1992) look promising as therapeutic agents. Finally, anxiety experienced during withdrawal has been implicated as a factor in relapse to drinking (Linnoila 1989). A promising new drug that reduces serotonergic neurotransmission, mianserin, blocks withdrawal-induced anxiety in animals (Prather et al. 1991) and has the advantage of being nonaddictive, with long-lasting effects that can be achieved in a single dose. However, many laboratory-tested drugs such as mianserin have not yet been tested clinically.

Chronic Effects of Alcohol

Three categories of organic brain disease associated with chronic alcoholism have been distinguished in the recent literature based on neuropsychological profiles: the WernickeKorsakoff syndrome, alcoholic dementia, and "nonamnesic" or "non-Korsakoff" disorders. The basic distinction among these groups is the presence or absence of amnesia and the severity of intellectual decline. The best known of these syndromes, the Wernicke-Korsakoff syndrome, is characterized by an acute Wernicke's phase in which patients exhibit clinical symptoms of mental confusion, oculomotor abnormalities, and ataxia. If patients are given thiamine, the oculomotor palsies and ataxia disappear in most cases (Victor et al. 1971). However, 80 percent of alcoholic patients who recover from Wernicke's encephalopathy are left with a residual severe memory disturbance known as Korsakoff syndrome (Victor et al. 1989). The memory deficits of alcoholics with Korsakoff syndrome have been well documented (Butters and Stuss 1988; Heindel et al. 1991; Ryan and Butters 1986; Salmon and Butters 1987), and, in general, are characterized by severe memory impairment in the presence of relatively normal intellectual ability. The ability to learn and retain skill-based information such as learning a purely visuomotor task is also preserved (see Butters and Stuss 1988 for a review). In the terminology of cognitive neuropsychology (Cohen 1984; Schacter et al. 1988), explicit, episodic, or declarative memory is impaired (that is, the ability to consciously or intentionally recall specific episodes or facts), while implicit, semantic, or procedural memory is intact (the patient is able to benefit from previous experiences that unconsciously facilitate performance). Although there is little neuropsychological evidence, improvement in memory over several months or even years of abstinence has been noted (Victor and Adams 1985).

Korsakoff patients also show impairments in several other areas of neuropsychological functioning, including sensory processing, visuospatial abilities, arousal, motivational and emotional functions, and maintaining appropriate responses (Ellis and Oscar-Berman 1989; Oscar-Berman et al. 1990).

Alcoholic dementia is distinguished from Wernicke-Korsakoff syndrome by global intellectual deterioration in addition to severe memory impairment (Cutting 1978, 1985; Lishman 1986).