6 Endocrine Effects of Alcohol JOHN
WRIGHT
The effect of alcohol on endocrine function has received increasing attention over recent years and there is now a considerable volume of literature on the subject. However, in addition to the common problems of assessing data obtained before the introduction of specific radioimmunoassays and of correlating results obtained from animal and human studies, interpretation of the literature is complicated by a number of problems. Extrapolation of data obtained from experiments involving acute administration of alcohol to long-term situations such as obtain in chronic alcoholism, and comparison of the response of habitual drinkers to alcohol with the response of alcohol-naive subjects, has led to confusion and apparently conflicting results. In addition, there has frequently been a failure to distinguish the endocrinological and metabolic effects of alcohol per se from those secondary to tissue and, particularly, liver damage; this is particularly relevant when considering the effect of alcohol on hypothalamic-pituitary-gonadal function. Finally, there has been a tendency to regard chronic alcoholics as a homogenous group regardless of differences in drinking patterns, the type and quantity of liquor consumed, the length history, nutritional status and the time interval between drinking and endocrine or metabolic studies, all of which may profoundly affect the results obtained. HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL AXIS Animal studies
Prior to the availability of direct hormone assays, studies of the effect of alcohol on adrenocortical function were based on indirect measurements such as adrenal cholesterol and ascorbic acid content, eosinophil counts and thymic involution. Several studies showed that acute administration of alcohol either by intragastric or intraperitoneal routes resulted in a fall in adrenal cholesterol and ascorbic acid content which was abolished by hypophysectomy and was not altered by the simultaneous administration of local anaesthetic when given intraperitoneally (Smith, 1951; Forbes and Duncan, 1951, 1953; Czaja and Kalant, 1961). Direct evidence of adrenocortical stimulation was first provided by Ellis (1966) who showed that following intraperitoneal injection of alcohol in rats, there was a dose-related Clinics in E n d o c r i n o l o g y a n d M e t a b o l i s m - -
Vol. 7, No. 2, July 1978.
351
352
JOHN WRIGHT
increase in plasma corticosterone with a significant increase occurring at a blood alcohol concentration of only 7.3 mmol/1 (33.5 mg/100 ml) and a five-fold increase with a blood alcohol concentration above 87 mmol/1 (400 mg/100 ml). There was no response in hypophysectomized animals, nor in animals pre-treated with either morphine or phenobarbitone. Direct evidence that the adrenocortical response to alcohol is mediated via ACTH was provided by Noble, Kakihana and Butte (1971) who found a fall in pituitary ACTH concentration occurring 10 minutes after acute administration of alcohol to mice. Tolerance to repeated administration of alcohol has been investigated by a number of workers. Ellis (1966) studied a group of rats given an intraperitoneal injection of alcohol (2 g/kg) daily for seven days. On the eighth day the acute plasma corticosterone response to a further injection of alcohol was only slightly less than in unconditioned animals. However, there is some evidence that pre-treatment may reduce the adrenocortical response to acute administration of alcohol. Crossland and Ratcliffe (1968) found that the plasma corticosterone response to a single intraperitoneal injection of alcohol was reduced in rats which had received alcohol in their drinking water for several weeks. They also found a reduced corticosterone response to a number of other stressful stimuli. Noble, Kakihana and Butte (1971) also demonstrated a reduced corticosterone response to alcohol in alcohol-adapted mice when measured one hour after intraperitoneal injection. However, the peak corticosterone response was similar to, but earlier than, that seen in saline-treated animals. This was not due to changes in corticosterone metabolism or adrenal responsiveness to ACTH nor to changes in peak levels or disappearance rates of blood alcohol all of which were similar in both controls and alcohol-adapted animals. Chronic administration of alcohol to experimental animals has also been shown to abolish the diurnal variation in plasma corticosterone, resulting in a plateau level approximately midway between normal peak and trough levels (Kakihana and Moore, 1975). This finding has obvious implications whenever comparisons are made between blood levels of corticosterone (and presumably cortisol) in drinking and non-drinking animals. It has recently been suggested that glucocorticoids may play a permissive role in the development of both dependence upon and tolerance to alcohol. In mice given alcohol for two or three weeks, the incidence of withdrawal seizures (taken as evidence for physical dependence) was reduced from 40 to 16 per cent by adrenalectomy (Sze, Yanai and Ginsburg, 1974). Adrenalectomy also abolished the increase in liver alcohol dehydrogenase activity found in mice given alcohol for two weeks although it had no effect on the induction of liver microsomal ethanol oxidizing system (MEOS) (Sze, 1975). In addition, rats injected daily with dexamethasone and ethanol showed antagonism to the acute effects of alcohol and a higher rate of tolerance to its depressant effects than rats treated with ethanol alone (Wood, 1977). Studies in m a n
Early studies in normal subjects failed to detect any consistent change in urinary steroid output following acute alcohol ingestion (Kissin, Schenker
ENDOCRINE EFFECTS OF ALCOHOL
353
and Schenker, 1960; Perman, 1961). Fazekas (1966) gave alcohol (1.0 or 1.5 g/kg) as wine to five male volunteers. Blood alcohol rose above 22 mmol/1 (100 mg/100 ml) in all subjects and this was associated with a rise in plasma cortisol which was more marked with the larger dose. Jenkins and Connolly (1968) also demonstrated dose-dependent stimulation of adrenocortical secretion. They gave alcohol intravenously, 1 mg/kg over 30 minutes, to 1S normal volunteers. A significant rise in plasma cortisol was seen in all subjects in whom blood alcohol rose above 22 mmol/1 (100 mg/100 ml); no rise was observed in the remainder. Pre-treatment with morphine, which inhibits the pituitary response to vasopressin, had no effect on the cortisol response to alcohol but there was no response in two patients with hypopituitarism. These findings have since been confirmed by several authors (Merry and Marks, 1969; Bellet et al, 1970, 1971). The situation in alcoholics is more complex. Basal plasma cortisol levels are elevated in recently drinking alcoholics (Margraf et al, 1967; Merry and Marks, 1969) and normal in abstinent alcoholics (Mendelson and Stein, 1966; Mendelson, Ogata and Mello, 1971). Merry and Marks (1969) showed that in alcoholics, abolition of withdrawal symptoms by administration of alcohol (284 ml whisky) resulted in a fall in plasma cortisol in contrast to the rise produced in normal control subjects. Treatment with amylobarbitone in a dose sufficient to relieve withdrawal symptoms also resulted in a fall in plasma cortisol. However, treatment with diazepam, which produced similar alleviation of withdrawal symptoms, resulted in no change in plasma cortisol (Merry and Marks, 1972). These findings suggest that the hypercortisolaemia seen in acutely withdrawn alcoholics is not solely due to non-specific stress but may be associated with a more specific effect on autonomic regulatory centres. More prolonged administration of alcohol to chronic alcoholics has been shown to result in adrenocortical stimulation. Mendelson, Ogata and Mello (1971) studied four chronic alcoholics with no evidence of liver disease who had been abstinent for at least 60 days. Basal plasma cortisol levels were normal but during a period of drinking (up to 4 g/kg alcohol daily) for between 11 and 29 days there was a consistent increase in plasma cortisol which correlated fairly well with the blood alcohol level. In a similar study on 18 alcoholic subjects, Stokes (1973) also found a rise in plasma cortisol during a prolonged period of drinking but failed to observe a close correlation between the levels of blood alcohol and plasma cortisol. The reduction in cortisol levels in chronic alcoholics following a single dose of alcohol may reflect the situation in 'relief drinking'. However, as Mendelson (1970) has pointed out, chronic alcohol intake may be associated with increasing anxiety and depression which, along with the physiological stress of chronic intoxication, might be expected to result in persistent elevation of plasma cortisol. It has been recognized for some time that chronic alcoholics may develop physical stigmata resembling those of Cushing's syndrome and that this may lead to confusion between the two conditions (Dillon, 1973; Merry and Marks, 1973). Recently, a number of well-documented cases of alcoholinduced 'pseudo Cushing's syndrome' have been reported (Smals et al, 1976;
354
JOHN WRIGHT
Rees et al, 1977; Paton, 1976; Frajria and Angeli, 1977; Smals et al, 1977). The clinical picture in these cases may be virtually indistinguishable from that of true Cushings' syndrome. In addition to characteristic Cushingoid facies, physical features may include arterial hypertension, muscle wasting, a buffalo hump, abdominal striae, easy bruising and vertebral collapse. Biochemical findings are variable but have included glucose intolerance and hypercortisolaemia with inadequate dexamethasone suppression and impaired diurnal variation; urinary steroids are increased; plasma ACTH levels may be inappropriately elevated and may fail to show normal diurnal variation. Smals and Kloppenberg (1977) found that there was no significant difference in serum aspartate transaminase (SGOT) activity between Cushingoid and non-Cushingoid alcoholics, suggesting that the hypercortisolaemia is not the result of impaired liver function. Abnormal biochemical findings rapidly return to normal following abstinence from alcohol but tend to reappear with resumption of drinking. The cause of this syndrome is uncertain; it presumably results from prolonged adrenal hyperstimulation in response to the stress of chronic intoxication and increased sensitivity of peripheral tissues to cortisol in susceptible subjects. It has also been suggested (Frajria and Angeli, 1977) that the level of cortisol-binding globulin may be reduced in these patients, resulting in an increase in the fraction of biologically active cortisol. The pitfalls in investigating patients with Cushing's syndrome too soon after admission to hospital are well recognized and are generally attributed to stress-induced increases in corticosteroid levels. In a proportion of patients, alcohol-induced elevation of corticosteroid values may be partly responsible for these 'false-positive' results. Because of the frequency of this syndrome, alcohol abuse must always be considered in the differential diagnosis of Cushing's syndrome. Paradoxically, there is increasing recognition of a characteristic type of acquired and seemingly reversible syndrome of hypothalamic-pituitaryadrenocortical insufficiency peculiar to chronic alcoholism. The existence of such a syndrome was proposed almost thirty years ago (Tintera and Lovell, 1949; Smith, 1950) but scientific evidence was then lacking and claims for the efficacy of treatment with ACTH and adrenocortical extract, which was later shown to possess little or no biologically active glucocorticoids (Journal of Clinical Endocrinology and Metabolism editorial, 1973), are of dubious merit. Selective ACTH deficiency was initially described in chronic alcoholics presenting with alcohol-induced hypoglycaemia (Freinkel et al, 1963; Woeber and Arky, 1965). Treatment with cortisone prevented the development of alcohol-induced hypoglycaemia, suggesting that this was not solely due to impaired gluconeogenesis resulting from liver damage. In the one patient tested, there was no response to metyrapone. More recent studies indicate that this syndrome is common in unselected alcoholics without evidence of severe liver disease. Adrenocortical reserve (as assessed by response to ACTH stimulation) is normal in these patients (Merry and Marks, 1969; Wright, 1974). However, in about 25 per cent of chronic alcoholics the cortisol response to insulin-induced hypoglycaemia is
ENDOCRINE EFFECTSOF ALCOHOL
355
either absent or severely attenuated (Merry and Marks, 1973; Wright, 1974; Chalmers et al, 1977) and there may be no associated sympathetic response to hypoglycaemia assessed clinically (Wright, 1974). Similarly, an impaired adrenocortical response to surgical stress has been reported (Margraf et al, 1967). In the one patient re-examined after six months abstinence from alcohol, the cortisol response to hypoglycaemia was normal on retesting (Merry and Marks, 1973). The importance of this syndrome in the pathogenesis of alcohol-induced hypoglycaemia is discussed elsewhere (see Chapter 5). On the basis of current evidence it is not possible to decide whether the impaired hypothalamicpituitary-adrenocortical response to hypoglycaemia represents a specific action of alcohol or an adaptation to chronic stress as occurs, for example, in animals made repeatedly hypoglycaemic by injection of insulin (Kraicer and Logethetopoulos, 1963). In some subjects the impaired cortisol response may be associated with diminished growth hormone and catecholamine response (q.v.).
HYPOTHALAMIC-PITUITARY-GONADAL FUNCTION Hepatic cirrhosis in men is commonly associated with both hypogonadism and feminization. The similarities between the endocrine features of alcoholic and non-alcoholic cirrhosis indicate that it is the liver disease itself which is responsible for these changes. A detailed discussion of the endocrine manifestations of cirrhosis is beyond the scope of this chapter. However, in view of the obvious relevance to the findings in alcoholic patients, the main biochemical changes which have been described are listed below; for further discussion and references, see the reviews by Adlercreutz (1974), van Thiel and Lester (1976) and Green (1977).
Biochemical basis for hypogonadism in cirrhosis 1. Decreased plasma concentration of total and free testosterone. 2. Decreased metabolic clearance and production rates of testosterone. 3. Decreased plasma concentration of dihydrotestosterone. 4. Increased sex hormone-binding globulin (increased androgen binding). 5. Impaired testosterone response to HCG stimulation. 6. Variable basal gonadotrophin levels (high, low or normal). 7. Impaired gonadotrophin (and testosterone) response to clomiphene stimulation. Biochemical basis for feminization in cirrhosis 1. Normal or increased plasma oestradiol. 2. Increased plasma oestrone. 3. Increased plasma concentration and production rate of androstenedione. 4. Increased conversion of androgens to oestrogens (androstenedione to oestrone and testosterone to oestradiol). 5. Decreased serum albumin (decreased oestrogen binding). 6. Increased serum prolactin (?).
356
JOHN WRIGHT
In contrast, the influence of alcohol itself on gonadal function has received relatively little attention, although recent studies have produced evidence for specific effects independent of liver dysfunction. Animal studies
Intravenous administration of alcohol to oestrous rabbits prior to mating produced a fall in the number of subsequent litters compared with a control group (Chaudhury and Matthews, 1966). This effect was apparently not due to inhibition of ovulation as assessed by the number of bleeding points on the ovaries of a further group of rabbits similarly treated and sacrificed following mating. However, alcohol may inhibit oestrous in mice (Cranston, 1958) and it has been shown to inhibit ovulation in rats, an effect which can be reversed by administration of LH (Kieffer and Ketchell, 1970). In male animals there is increasing evidence for inhibition of testosterone secretion by alcohol. In a group of mice given alcohol daily for five days via stomach tube, Badr and Bartke (1974) found a dose-dependent fall in plasma testosterone levels but no change in testicular weight. Administration of alcohol to rats for a longer period (41 days) resulted in a similar, marked fall in plasma testosterone associated with a reduction in testicular weight largely due to a reduction in seminiferous tubule diameter and in the amount of germinal epiethelium (Van Thiel et al, 1975). A similar reduction in testosterone accompanied by a marked rise in plasma LH levels was observed by Fry et al (1977, unpublished observations) in rats given alcohol for 58 weeks. Furthermore, alcohol given to rats from the third to the tenth week of life almost completely abolishes the increase in basal LH levels which occurs during normal maturation (Symons and Marks, 1975). Studies in man
In normal men there is no change in plasma testosterone within the first few hours of alcohol ingestion (Toro et al, 1973). However, Ylikahri et al (1974) found that plasma testosterone fell 12 hours after acute ingestion of alcohol (1.5 g/kg over three hours); at 20 hours, the mean level was less than half the value found during a control experiment (water only). More recently, Gordon et al (1976) investigated the effect of long-term drinking on normal subjects. Eleven men were given alcohol, 3 g/kg daily in divided doses for 25 to 28 days. Despite this fairly large dose of alcohol (equivalent to about three bottles of wine daily) the subjects were 'never grossly intoxicated'. Results from this comprehensive study showed a marked increase in hepatic testosterone A-ring reductase activity in all subjects, an increase in the metabolic clearance rate of testosterone in five of eight subjects, a fall in the production rate of testosterone in three of four subjects and a fall in the plasma testosterone-binding capacity in all subjects. Studies of plasma testosterone concentration showed a loss of pulsatile secretory episodes and a fall in the mean plasma concentration. The results for one subject are shown in Figure 1. Although there was no change in gonadotrophin levels as a group, in some subjects (see Figure 1) there was an increase in LH, suggesting a direct action of alcohol on testicular function. No change was found in the conversion rates of androgens (testosterone and androstenedione) to oestrogens.
ENDOCRINE EFFECTS OF ALCOHOL
357
|
.iS ~.
.
WRIGHT
The effect of alcohol on endocrine function has received increasing attention over recent years and there is now a considerable volume of literature on the subject. However, in addition to the common problems of assessing data obtained before the introduction of specific radioimmunoassays and of correlating results obtained from animal and human studies, interpretation of the literature is complicated by a number of problems. Extrapolation of data obtained from experiments involving acute administration of alcohol to long-term situations such as obtain in chronic alcoholism, and comparison of the response of habitual drinkers to alcohol with the response of alcohol-naive subjects, has led to confusion and apparently conflicting results. In addition, there has frequently been a failure to distinguish the endocrinological and metabolic effects of alcohol per se from those secondary to tissue and, particularly, liver damage; this is particularly relevant when considering the effect of alcohol on hypothalamic-pituitary-gonadal function. Finally, there has been a tendency to regard chronic alcoholics as a homogenous group regardless of differences in drinking patterns, the type and quantity of liquor consumed, the length history, nutritional status and the time interval between drinking and endocrine or metabolic studies, all of which may profoundly affect the results obtained. HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL AXIS Animal studies
Prior to the availability of direct hormone assays, studies of the effect of alcohol on adrenocortical function were based on indirect measurements such as adrenal cholesterol and ascorbic acid content, eosinophil counts and thymic involution. Several studies showed that acute administration of alcohol either by intragastric or intraperitoneal routes resulted in a fall in adrenal cholesterol and ascorbic acid content which was abolished by hypophysectomy and was not altered by the simultaneous administration of local anaesthetic when given intraperitoneally (Smith, 1951; Forbes and Duncan, 1951, 1953; Czaja and Kalant, 1961). Direct evidence of adrenocortical stimulation was first provided by Ellis (1966) who showed that following intraperitoneal injection of alcohol in rats, there was a dose-related Clinics in E n d o c r i n o l o g y a n d M e t a b o l i s m - -
Vol. 7, No. 2, July 1978.
351
352
JOHN WRIGHT
increase in plasma corticosterone with a significant increase occurring at a blood alcohol concentration of only 7.3 mmol/1 (33.5 mg/100 ml) and a five-fold increase with a blood alcohol concentration above 87 mmol/1 (400 mg/100 ml). There was no response in hypophysectomized animals, nor in animals pre-treated with either morphine or phenobarbitone. Direct evidence that the adrenocortical response to alcohol is mediated via ACTH was provided by Noble, Kakihana and Butte (1971) who found a fall in pituitary ACTH concentration occurring 10 minutes after acute administration of alcohol to mice. Tolerance to repeated administration of alcohol has been investigated by a number of workers. Ellis (1966) studied a group of rats given an intraperitoneal injection of alcohol (2 g/kg) daily for seven days. On the eighth day the acute plasma corticosterone response to a further injection of alcohol was only slightly less than in unconditioned animals. However, there is some evidence that pre-treatment may reduce the adrenocortical response to acute administration of alcohol. Crossland and Ratcliffe (1968) found that the plasma corticosterone response to a single intraperitoneal injection of alcohol was reduced in rats which had received alcohol in their drinking water for several weeks. They also found a reduced corticosterone response to a number of other stressful stimuli. Noble, Kakihana and Butte (1971) also demonstrated a reduced corticosterone response to alcohol in alcohol-adapted mice when measured one hour after intraperitoneal injection. However, the peak corticosterone response was similar to, but earlier than, that seen in saline-treated animals. This was not due to changes in corticosterone metabolism or adrenal responsiveness to ACTH nor to changes in peak levels or disappearance rates of blood alcohol all of which were similar in both controls and alcohol-adapted animals. Chronic administration of alcohol to experimental animals has also been shown to abolish the diurnal variation in plasma corticosterone, resulting in a plateau level approximately midway between normal peak and trough levels (Kakihana and Moore, 1975). This finding has obvious implications whenever comparisons are made between blood levels of corticosterone (and presumably cortisol) in drinking and non-drinking animals. It has recently been suggested that glucocorticoids may play a permissive role in the development of both dependence upon and tolerance to alcohol. In mice given alcohol for two or three weeks, the incidence of withdrawal seizures (taken as evidence for physical dependence) was reduced from 40 to 16 per cent by adrenalectomy (Sze, Yanai and Ginsburg, 1974). Adrenalectomy also abolished the increase in liver alcohol dehydrogenase activity found in mice given alcohol for two weeks although it had no effect on the induction of liver microsomal ethanol oxidizing system (MEOS) (Sze, 1975). In addition, rats injected daily with dexamethasone and ethanol showed antagonism to the acute effects of alcohol and a higher rate of tolerance to its depressant effects than rats treated with ethanol alone (Wood, 1977). Studies in m a n
Early studies in normal subjects failed to detect any consistent change in urinary steroid output following acute alcohol ingestion (Kissin, Schenker
ENDOCRINE EFFECTS OF ALCOHOL
353
and Schenker, 1960; Perman, 1961). Fazekas (1966) gave alcohol (1.0 or 1.5 g/kg) as wine to five male volunteers. Blood alcohol rose above 22 mmol/1 (100 mg/100 ml) in all subjects and this was associated with a rise in plasma cortisol which was more marked with the larger dose. Jenkins and Connolly (1968) also demonstrated dose-dependent stimulation of adrenocortical secretion. They gave alcohol intravenously, 1 mg/kg over 30 minutes, to 1S normal volunteers. A significant rise in plasma cortisol was seen in all subjects in whom blood alcohol rose above 22 mmol/1 (100 mg/100 ml); no rise was observed in the remainder. Pre-treatment with morphine, which inhibits the pituitary response to vasopressin, had no effect on the cortisol response to alcohol but there was no response in two patients with hypopituitarism. These findings have since been confirmed by several authors (Merry and Marks, 1969; Bellet et al, 1970, 1971). The situation in alcoholics is more complex. Basal plasma cortisol levels are elevated in recently drinking alcoholics (Margraf et al, 1967; Merry and Marks, 1969) and normal in abstinent alcoholics (Mendelson and Stein, 1966; Mendelson, Ogata and Mello, 1971). Merry and Marks (1969) showed that in alcoholics, abolition of withdrawal symptoms by administration of alcohol (284 ml whisky) resulted in a fall in plasma cortisol in contrast to the rise produced in normal control subjects. Treatment with amylobarbitone in a dose sufficient to relieve withdrawal symptoms also resulted in a fall in plasma cortisol. However, treatment with diazepam, which produced similar alleviation of withdrawal symptoms, resulted in no change in plasma cortisol (Merry and Marks, 1972). These findings suggest that the hypercortisolaemia seen in acutely withdrawn alcoholics is not solely due to non-specific stress but may be associated with a more specific effect on autonomic regulatory centres. More prolonged administration of alcohol to chronic alcoholics has been shown to result in adrenocortical stimulation. Mendelson, Ogata and Mello (1971) studied four chronic alcoholics with no evidence of liver disease who had been abstinent for at least 60 days. Basal plasma cortisol levels were normal but during a period of drinking (up to 4 g/kg alcohol daily) for between 11 and 29 days there was a consistent increase in plasma cortisol which correlated fairly well with the blood alcohol level. In a similar study on 18 alcoholic subjects, Stokes (1973) also found a rise in plasma cortisol during a prolonged period of drinking but failed to observe a close correlation between the levels of blood alcohol and plasma cortisol. The reduction in cortisol levels in chronic alcoholics following a single dose of alcohol may reflect the situation in 'relief drinking'. However, as Mendelson (1970) has pointed out, chronic alcohol intake may be associated with increasing anxiety and depression which, along with the physiological stress of chronic intoxication, might be expected to result in persistent elevation of plasma cortisol. It has been recognized for some time that chronic alcoholics may develop physical stigmata resembling those of Cushing's syndrome and that this may lead to confusion between the two conditions (Dillon, 1973; Merry and Marks, 1973). Recently, a number of well-documented cases of alcoholinduced 'pseudo Cushing's syndrome' have been reported (Smals et al, 1976;
354
JOHN WRIGHT
Rees et al, 1977; Paton, 1976; Frajria and Angeli, 1977; Smals et al, 1977). The clinical picture in these cases may be virtually indistinguishable from that of true Cushings' syndrome. In addition to characteristic Cushingoid facies, physical features may include arterial hypertension, muscle wasting, a buffalo hump, abdominal striae, easy bruising and vertebral collapse. Biochemical findings are variable but have included glucose intolerance and hypercortisolaemia with inadequate dexamethasone suppression and impaired diurnal variation; urinary steroids are increased; plasma ACTH levels may be inappropriately elevated and may fail to show normal diurnal variation. Smals and Kloppenberg (1977) found that there was no significant difference in serum aspartate transaminase (SGOT) activity between Cushingoid and non-Cushingoid alcoholics, suggesting that the hypercortisolaemia is not the result of impaired liver function. Abnormal biochemical findings rapidly return to normal following abstinence from alcohol but tend to reappear with resumption of drinking. The cause of this syndrome is uncertain; it presumably results from prolonged adrenal hyperstimulation in response to the stress of chronic intoxication and increased sensitivity of peripheral tissues to cortisol in susceptible subjects. It has also been suggested (Frajria and Angeli, 1977) that the level of cortisol-binding globulin may be reduced in these patients, resulting in an increase in the fraction of biologically active cortisol. The pitfalls in investigating patients with Cushing's syndrome too soon after admission to hospital are well recognized and are generally attributed to stress-induced increases in corticosteroid levels. In a proportion of patients, alcohol-induced elevation of corticosteroid values may be partly responsible for these 'false-positive' results. Because of the frequency of this syndrome, alcohol abuse must always be considered in the differential diagnosis of Cushing's syndrome. Paradoxically, there is increasing recognition of a characteristic type of acquired and seemingly reversible syndrome of hypothalamic-pituitaryadrenocortical insufficiency peculiar to chronic alcoholism. The existence of such a syndrome was proposed almost thirty years ago (Tintera and Lovell, 1949; Smith, 1950) but scientific evidence was then lacking and claims for the efficacy of treatment with ACTH and adrenocortical extract, which was later shown to possess little or no biologically active glucocorticoids (Journal of Clinical Endocrinology and Metabolism editorial, 1973), are of dubious merit. Selective ACTH deficiency was initially described in chronic alcoholics presenting with alcohol-induced hypoglycaemia (Freinkel et al, 1963; Woeber and Arky, 1965). Treatment with cortisone prevented the development of alcohol-induced hypoglycaemia, suggesting that this was not solely due to impaired gluconeogenesis resulting from liver damage. In the one patient tested, there was no response to metyrapone. More recent studies indicate that this syndrome is common in unselected alcoholics without evidence of severe liver disease. Adrenocortical reserve (as assessed by response to ACTH stimulation) is normal in these patients (Merry and Marks, 1969; Wright, 1974). However, in about 25 per cent of chronic alcoholics the cortisol response to insulin-induced hypoglycaemia is
ENDOCRINE EFFECTSOF ALCOHOL
355
either absent or severely attenuated (Merry and Marks, 1973; Wright, 1974; Chalmers et al, 1977) and there may be no associated sympathetic response to hypoglycaemia assessed clinically (Wright, 1974). Similarly, an impaired adrenocortical response to surgical stress has been reported (Margraf et al, 1967). In the one patient re-examined after six months abstinence from alcohol, the cortisol response to hypoglycaemia was normal on retesting (Merry and Marks, 1973). The importance of this syndrome in the pathogenesis of alcohol-induced hypoglycaemia is discussed elsewhere (see Chapter 5). On the basis of current evidence it is not possible to decide whether the impaired hypothalamicpituitary-adrenocortical response to hypoglycaemia represents a specific action of alcohol or an adaptation to chronic stress as occurs, for example, in animals made repeatedly hypoglycaemic by injection of insulin (Kraicer and Logethetopoulos, 1963). In some subjects the impaired cortisol response may be associated with diminished growth hormone and catecholamine response (q.v.).
HYPOTHALAMIC-PITUITARY-GONADAL FUNCTION Hepatic cirrhosis in men is commonly associated with both hypogonadism and feminization. The similarities between the endocrine features of alcoholic and non-alcoholic cirrhosis indicate that it is the liver disease itself which is responsible for these changes. A detailed discussion of the endocrine manifestations of cirrhosis is beyond the scope of this chapter. However, in view of the obvious relevance to the findings in alcoholic patients, the main biochemical changes which have been described are listed below; for further discussion and references, see the reviews by Adlercreutz (1974), van Thiel and Lester (1976) and Green (1977).
Biochemical basis for hypogonadism in cirrhosis 1. Decreased plasma concentration of total and free testosterone. 2. Decreased metabolic clearance and production rates of testosterone. 3. Decreased plasma concentration of dihydrotestosterone. 4. Increased sex hormone-binding globulin (increased androgen binding). 5. Impaired testosterone response to HCG stimulation. 6. Variable basal gonadotrophin levels (high, low or normal). 7. Impaired gonadotrophin (and testosterone) response to clomiphene stimulation. Biochemical basis for feminization in cirrhosis 1. Normal or increased plasma oestradiol. 2. Increased plasma oestrone. 3. Increased plasma concentration and production rate of androstenedione. 4. Increased conversion of androgens to oestrogens (androstenedione to oestrone and testosterone to oestradiol). 5. Decreased serum albumin (decreased oestrogen binding). 6. Increased serum prolactin (?).
356
JOHN WRIGHT
In contrast, the influence of alcohol itself on gonadal function has received relatively little attention, although recent studies have produced evidence for specific effects independent of liver dysfunction. Animal studies
Intravenous administration of alcohol to oestrous rabbits prior to mating produced a fall in the number of subsequent litters compared with a control group (Chaudhury and Matthews, 1966). This effect was apparently not due to inhibition of ovulation as assessed by the number of bleeding points on the ovaries of a further group of rabbits similarly treated and sacrificed following mating. However, alcohol may inhibit oestrous in mice (Cranston, 1958) and it has been shown to inhibit ovulation in rats, an effect which can be reversed by administration of LH (Kieffer and Ketchell, 1970). In male animals there is increasing evidence for inhibition of testosterone secretion by alcohol. In a group of mice given alcohol daily for five days via stomach tube, Badr and Bartke (1974) found a dose-dependent fall in plasma testosterone levels but no change in testicular weight. Administration of alcohol to rats for a longer period (41 days) resulted in a similar, marked fall in plasma testosterone associated with a reduction in testicular weight largely due to a reduction in seminiferous tubule diameter and in the amount of germinal epiethelium (Van Thiel et al, 1975). A similar reduction in testosterone accompanied by a marked rise in plasma LH levels was observed by Fry et al (1977, unpublished observations) in rats given alcohol for 58 weeks. Furthermore, alcohol given to rats from the third to the tenth week of life almost completely abolishes the increase in basal LH levels which occurs during normal maturation (Symons and Marks, 1975). Studies in man
In normal men there is no change in plasma testosterone within the first few hours of alcohol ingestion (Toro et al, 1973). However, Ylikahri et al (1974) found that plasma testosterone fell 12 hours after acute ingestion of alcohol (1.5 g/kg over three hours); at 20 hours, the mean level was less than half the value found during a control experiment (water only). More recently, Gordon et al (1976) investigated the effect of long-term drinking on normal subjects. Eleven men were given alcohol, 3 g/kg daily in divided doses for 25 to 28 days. Despite this fairly large dose of alcohol (equivalent to about three bottles of wine daily) the subjects were 'never grossly intoxicated'. Results from this comprehensive study showed a marked increase in hepatic testosterone A-ring reductase activity in all subjects, an increase in the metabolic clearance rate of testosterone in five of eight subjects, a fall in the production rate of testosterone in three of four subjects and a fall in the plasma testosterone-binding capacity in all subjects. Studies of plasma testosterone concentration showed a loss of pulsatile secretory episodes and a fall in the mean plasma concentration. The results for one subject are shown in Figure 1. Although there was no change in gonadotrophin levels as a group, in some subjects (see Figure 1) there was an increase in LH, suggesting a direct action of alcohol on testicular function. No change was found in the conversion rates of androgens (testosterone and androstenedione) to oestrogens.
ENDOCRINE EFFECTS OF ALCOHOL
357
|
.iS ~.
.
