AMERICAN JOURNAL OF EPIDEMIOLOGY
VOL 108, No. 3
Copyright © 1978 by The Johns Hopkins University School of Hygiene and Public Health Allrightsreserved
Printed in U.S.A.
THE RELATIONSHIP BETWEEN ALCOHOL, LIVER DISEASE, AND TESTICULAR PATHOLOGY LEWIS H. KULLER,1 SUSAN J. MAY' AND JOSHUA A. PERPER2 Kuller, L. H. (U. of Pittsburgh, Graduate School of Public Health, 130 DeSoto Street, Pittsburgh, PA 15261), S. J. May and J. A. Perper. The relationship between alcohol, liver disease, and testicular pathology. Am J Epidemiol 108:192-199, 1978. Impotence, Infertility and feminlzation have been frequently reported among male cirrhotlc patients. Previous studies have suggested that liver disease was the basis of these effects. Recent clinical and laboratory experimental studies have suggested that alcohol consumption may have a direct effect on both testosterone metabolism and spermatogenesls. The effect may be mediated through the central nervous system or directly on the testes. The present study compared the pathology in the liver and testes and the estimated alcohol consumption among men who had died suddenly from a variety of causes. Of 137 men studied, 20 (14%) had moderate to severe decrease In spermatogenesls. Only 9 of 19 with decreased spermatogenesls also had severe or very severe fatty infiltration of the liver. However, 17 of 19 were classified as heavy alcohol drinkers and 14 were estimated to consume at least 417 gm of alcohol per week. Finally, the alcohol history was reviewed In relation to liver and testicular pathology. Only a weak association between the liver and testes pathology was noted. alcohol; cirrhosis; liver disease; testosterone
Many studies have reported a relationship between "sexual function" and cirrhosis of the Liver. Until recently it was believed that failure to detoxify estrogen or increase conversion of testosterone to estrogen by the cirrhotic liver was the pathophysiologic basis for the feminization and testicular atrophy frequently reported among male alcoholics with liver disease, More recent studies have suggested that this model may not be correct. There are two basic functions of the testes that might be influenced by alcohol consumption (1): a) Production and matu-
ration of spermatozoa by the seminiferous tubules and b) the secretion of androgeri by the Leydig cells. Four types of studies have been reported: 1) Post mortem investigations of deaths due to cirrhosis have generally noted a high prevalence of testicular atrophy (2). The extent of testicular atrophy was apparently related to the activity of cirrhosis (3) and the severity of the liver disease (4, 5). 2) Studies of men with chronic liver disease have shown reduced plasma testosterone levels (6-11). The decrease was most striking among men with cirrhosis of the liver (6). The sex hormone binding globulin
1
Department of Epidemiology, University of Pitte- have also noted that both the metabolic burgh, Graduate School of Public Health, 130 DeSoto clearance and production of testosterone
S S f S S i
6
Total
7 27 15 S 42 100
4 18 11 4 13 50
i 7 1
2 4 15
2 2 3 2 9 16
1 7 10
6 6
3 3
much alcohol, 14 (31 per cent) had at least a moderate decrease in spermatogenesis. The relationship between alcohol consumption, age, race and testicular pathology was investigated by dichotomizing the alcohol consumption into two groups, less than or more than 417 gm per week, the minimal dose associated with severe or very severe decreased spermatogenesis (table 8). There was no apparent relationship between alcohol consumption and decreased spermatogenesis below the age of 45. There were, however, only thirteen heavy consumers of alcohol in this age group. There is also a suggestion that blacks had a higher prevalence of decreased spermatogenesis
197
ALCOHOL, LIVER DISEASE, AND TESTICULAK PATHOLOGY TABLE 7
Distribution of decreased spermatogenesis by estimated weekly alcohol consumption in grams (distribution divided into approximate thirds), Allegheny County, Pennsylvania, July 1, 1974-December 1,1975 Decreased spermatogenesis Consumption per week
Total
None
Minimal
Slight
Moderate
Severe
33 31 29 93
21 19 7 47
7 2 4 13
3 5 7 15
2 3 5 10
2 3 5
Low (0-26 gm) Middle (26-934 gm) High (==935 gm) Total
Very severe
3 •
3
TABLE 8
TABLE 9
Distribution of moderate to very severe decrease in spermatogenesis in iestes by age, race and estimated grams of ethanol consumed per week, Allegheny County, Pennsylvania, July 1, 1974-December 1, 1975
Distribution of fatty liver and decreased spermatogenesis by alcohol consumption, Allegheny County, Pennsylvania, July 1, 1974-December 1, 1975
Age (years)
35-44 45-54 Total
Race
White Black White Black
417gm moderate to severe decreased spermatogenesis
Total
No.
*
Total
No.
*
13
1 1 2 0 4
8 100 8 0 9
10 3 15 8 36
1 1 6 5 13
10 33 40 63 36
1
26 4
44
than whites after the relatively crude adjustment for alcohol consumption. Clearly, the sample size is too small for more detailed analysis. Fatty liver and decreased spermatogenesis were both related to alcohol consumption. The alcohol consumption history was subjectively classified by the interviewer as previously described. The extent of liver and testicular pathology was then quantified within each, classification of alcohol consumption. Fatty liver was classed as moderate, severe, or very severe (table 9). There was only a weak relationship between the liver and testicular pathology. Of the sixteen men in whom decreased spermatogenesis was associated with some alcohol consumption, only eight had fatty liver, while one-third of the heavy drinkers without decreased spermatogenesis had severe or very severe fatty liver. Cirrhosis of the liver has been related to testicular atrophy. Among 20 subjects with
Alcohol consumption None
Infrequent
Low
Moderate
Heavy
Total
Fatty liver
Decreased spermatogenesist
Total
Yes No
2 3
0 1
33
Yes No
0 6
0 2
33
Yes No
0 19
0 7
37
Yes No
0 15
0 5
33
Yes No
16 33
8 11
50 33
94
34
36
Yes-
• Fatty liver severe-very severe, t Decreased spennatogenesis: moderate-very severe.
moderate to very severe decrease of spermatogenesis, only two had cirrhosis of the liver at post mortem examination. The 94 non-traumatic death subjects were divided into five categories by cause of death and whether fatty, liver was also present. The prevalence of decreased spermatogenesis was evaluated within each of these groups. It was not associated with any specific cause of death and only modestly with the presence or absence of a fatty liver (table 10).
198
KULLER, MAY AND PERPER TABLE 10
Relationship of cause of death and presence of fatty liver to prevalence of decreased spermatogenesis, Allegheny County, Pennsylvania, July 1,1974-December 1, 1975 Moderate to very severe decreased spermatogenesis
Fatty liver*
No.
No.
%
Atherosclerotic heart disease
Yes No
27 28
4 3
15 11
Fatty liver
Yes No
4
2
50
Other natural causes
Yes No
15 20
5 4
33 20
94
18
19
Cause of death
Total
• Fatty liver moderate to very severe. DISCUSSION
The results of this study suggest that alcohol consumption was related to decreased spermatogenesis. The testicular pathology was apparently independent of overt liver disease. Although quantification of alcohol consumption is extremely difficult, the majority of subjects with moderate to severe decreased spermatogenesis had consumed at least 417 gm of ethanol per week, an average of 32 drinks per week of whiskey, wine or beer. Five or six 12 oz bottles of beer per night is not an extremely unusual consumption pattern. Clearly, however, the relationship between dose, duration and intensity of consumption and testicular pathology, reduction of testosterone level, sterility, impotence and feminizatdon needs further evaluation. Mechanisms for decreased spermatogenesis and spermiogenesis as well as impotence and feminization have been suggested by several authors. The major question remains whether the changes in the testes are primary or secondary to liver disease. Moreover, the interesting hypothesis relating vitamin A and alcohol dehydrogenase to sterility proposed by Lester and Van Thiel (16) needs further evaluation in man.
The gross pathologic changes in the testes noted in this study were not associated in most cases with liver pathology. However, specific metabolic changes in the liver could occur without overt pathologic signs. The results of this study were consistent with the studies of Van Thiel, Lester (8, 9) and others suggesting a direct effect of alcohol on the testes. The epidemiology of impotence and sterility in man has not been adequately studied, as noted in a recent review article (19). Of particular interest may be the synergistic effect of alcohol and other drugs such as antihypertensive agents, as well as such diseases as diabetes and atherosclerosis, in the pathogenesis of impotence and. sterility. Also the relationship of alcohol consumption with other diseases could possibly be mediated by the effect of alcohol on testosterone concentration. The ratio of estrogen to testosterone may be related to the reported association of alcohol with lipoprotein distribution, risk of heart attack or certain cancers. REFERENCES
1. Van Thiel DH, Lester R: Progress in hepatology, alcoholism: Its effect on hypothalamic pituitary gonadal function. Gaatroenterology 71:318-327, 1976 2. Morrione TG: Effect of estrogens on the testis in hepatic insufficiency. Arch Pathol 37:39-48, 1944 3. Rather LJ: Hepatic cirrhosis and testicular atrophy. Arch Intern Med 80:397-402, 1947 4. Lloyd CW, Williams RH: Clinical studies: Endocrine changes associated with Laennec's cirrhosis of the liver. Am J Med 4:315-330, 1948 5. Bennett HS, Baggenstoas AH, Butt HR: The testis, breast and prostate of men who die of cirrhosis of the liver. Am J Clin Pathol 20:814-828, 1950 6. Galvao-Teles A, Burke CW, Anderson DC, et al: Biologically active androgens and estradiol in men with chronic liver disease. Lancet 1:173-177, 1973 7. Southren AL, Gordon GG, Olivo J, et aL Androgen metabolism in cirrhosis of the liver. Metabolism 22:695-702, 1973 8. Van Thiel DH, Sherins RJ, Lester R: Mechanism of hypogonadism in alcoholic liver disease. Gastroenterology 65:574, 1973 9. Van Thiel DH, Lester R, Sherins RJ: Hypogonadism in alcoholic liver disease: Evidence for a double defect. Gastroenterology 67:1188-1199, 1974 10. Van Thiel DH, Gavaler JS, Lester R, et al: Plasma estrone, prolactin neyrophysin, and sex steroidbinding globulin in chronic alcoholic men. Metab-
ALCOHOL, LIVER DISEASE, AND TESTICULAR PATHOLOGY olism 24:1015-1019, 1975 11. Kley HK, Nieschkg E, Wiegelmann W: Steroid hormones and their binding in plasma of male patients with fatty liver, chronic hepatitis and liver cirrhosis. Acta Endocrinol 79-^75-285, 1975 12. Huttunen MO, Harkonen M, Niskanen P, et al: Plasma testosterone concentration in alcoholics. J Stud Alcohol 37:1165-1177, 1976 13. Lemere F, Smith JW: Alcohol-induced sexual impotence. Am J Psychiatry 130:212-213, 1973 14. Ylikahri R, Huttunen M, Harkonen M, et a l Low plasma testosterone values in men during hangover. J Steroid Biochem 5:655-658, 1974 15. Gordon GG, Altaian K, Southren AL, et al: Effect of alcohol. (ethanol) administration on sex-hor-
16.
17.
18. 19.
199
mone metabolism in normal men. N Engl J Med 295:793-797, 1976 Van Thiel DH, Gavaler J, Lester R Ethanol inhibition of vitamin A metabolism in the testes: Possible mechanism for sterility in alcoholics. Science 186541-942, 1974 Van Thiel DH, Gavaler JS, Lester R, et al: Alcohol-induced testicular atrophy: An experimental model for hypogonadism occurring in chronic alcoholic men. Gastroenterology 69:326-332, 1975 Cahalan D, Room R: Problem Drinking among American Men. New Brunswick, NJ, Rutgers Center of Alcohol Studies, 1973 Levine SB: Marital sexual dysfunction: Erectile dysfunction. Ann Intern Med 85:342-350,1976
VOL 108, No. 3
Copyright © 1978 by The Johns Hopkins University School of Hygiene and Public Health Allrightsreserved
Printed in U.S.A.
THE RELATIONSHIP BETWEEN ALCOHOL, LIVER DISEASE, AND TESTICULAR PATHOLOGY LEWIS H. KULLER,1 SUSAN J. MAY' AND JOSHUA A. PERPER2 Kuller, L. H. (U. of Pittsburgh, Graduate School of Public Health, 130 DeSoto Street, Pittsburgh, PA 15261), S. J. May and J. A. Perper. The relationship between alcohol, liver disease, and testicular pathology. Am J Epidemiol 108:192-199, 1978. Impotence, Infertility and feminlzation have been frequently reported among male cirrhotlc patients. Previous studies have suggested that liver disease was the basis of these effects. Recent clinical and laboratory experimental studies have suggested that alcohol consumption may have a direct effect on both testosterone metabolism and spermatogenesls. The effect may be mediated through the central nervous system or directly on the testes. The present study compared the pathology in the liver and testes and the estimated alcohol consumption among men who had died suddenly from a variety of causes. Of 137 men studied, 20 (14%) had moderate to severe decrease In spermatogenesls. Only 9 of 19 with decreased spermatogenesls also had severe or very severe fatty infiltration of the liver. However, 17 of 19 were classified as heavy alcohol drinkers and 14 were estimated to consume at least 417 gm of alcohol per week. Finally, the alcohol history was reviewed In relation to liver and testicular pathology. Only a weak association between the liver and testes pathology was noted. alcohol; cirrhosis; liver disease; testosterone
Many studies have reported a relationship between "sexual function" and cirrhosis of the Liver. Until recently it was believed that failure to detoxify estrogen or increase conversion of testosterone to estrogen by the cirrhotic liver was the pathophysiologic basis for the feminization and testicular atrophy frequently reported among male alcoholics with liver disease, More recent studies have suggested that this model may not be correct. There are two basic functions of the testes that might be influenced by alcohol consumption (1): a) Production and matu-
ration of spermatozoa by the seminiferous tubules and b) the secretion of androgeri by the Leydig cells. Four types of studies have been reported: 1) Post mortem investigations of deaths due to cirrhosis have generally noted a high prevalence of testicular atrophy (2). The extent of testicular atrophy was apparently related to the activity of cirrhosis (3) and the severity of the liver disease (4, 5). 2) Studies of men with chronic liver disease have shown reduced plasma testosterone levels (6-11). The decrease was most striking among men with cirrhosis of the liver (6). The sex hormone binding globulin
1
Department of Epidemiology, University of Pitte- have also noted that both the metabolic burgh, Graduate School of Public Health, 130 DeSoto clearance and production of testosterone
S S f S S i
6
Total
7 27 15 S 42 100
4 18 11 4 13 50
i 7 1
2 4 15
2 2 3 2 9 16
1 7 10
6 6
3 3
much alcohol, 14 (31 per cent) had at least a moderate decrease in spermatogenesis. The relationship between alcohol consumption, age, race and testicular pathology was investigated by dichotomizing the alcohol consumption into two groups, less than or more than 417 gm per week, the minimal dose associated with severe or very severe decreased spermatogenesis (table 8). There was no apparent relationship between alcohol consumption and decreased spermatogenesis below the age of 45. There were, however, only thirteen heavy consumers of alcohol in this age group. There is also a suggestion that blacks had a higher prevalence of decreased spermatogenesis
197
ALCOHOL, LIVER DISEASE, AND TESTICULAK PATHOLOGY TABLE 7
Distribution of decreased spermatogenesis by estimated weekly alcohol consumption in grams (distribution divided into approximate thirds), Allegheny County, Pennsylvania, July 1, 1974-December 1,1975 Decreased spermatogenesis Consumption per week
Total
None
Minimal
Slight
Moderate
Severe
33 31 29 93
21 19 7 47
7 2 4 13
3 5 7 15
2 3 5 10
2 3 5
Low (0-26 gm) Middle (26-934 gm) High (==935 gm) Total
Very severe
3 •
3
TABLE 8
TABLE 9
Distribution of moderate to very severe decrease in spermatogenesis in iestes by age, race and estimated grams of ethanol consumed per week, Allegheny County, Pennsylvania, July 1, 1974-December 1, 1975
Distribution of fatty liver and decreased spermatogenesis by alcohol consumption, Allegheny County, Pennsylvania, July 1, 1974-December 1, 1975
Age (years)
35-44 45-54 Total
Race
White Black White Black
417gm moderate to severe decreased spermatogenesis
Total
No.
*
Total
No.
*
13
1 1 2 0 4
8 100 8 0 9
10 3 15 8 36
1 1 6 5 13
10 33 40 63 36
1
26 4
44
than whites after the relatively crude adjustment for alcohol consumption. Clearly, the sample size is too small for more detailed analysis. Fatty liver and decreased spermatogenesis were both related to alcohol consumption. The alcohol consumption history was subjectively classified by the interviewer as previously described. The extent of liver and testicular pathology was then quantified within each, classification of alcohol consumption. Fatty liver was classed as moderate, severe, or very severe (table 9). There was only a weak relationship between the liver and testicular pathology. Of the sixteen men in whom decreased spermatogenesis was associated with some alcohol consumption, only eight had fatty liver, while one-third of the heavy drinkers without decreased spermatogenesis had severe or very severe fatty liver. Cirrhosis of the liver has been related to testicular atrophy. Among 20 subjects with
Alcohol consumption None
Infrequent
Low
Moderate
Heavy
Total
Fatty liver
Decreased spermatogenesist
Total
Yes No
2 3
0 1
33
Yes No
0 6
0 2
33
Yes No
0 19
0 7
37
Yes No
0 15
0 5
33
Yes No
16 33
8 11
50 33
94
34
36
Yes-
• Fatty liver severe-very severe, t Decreased spennatogenesis: moderate-very severe.
moderate to very severe decrease of spermatogenesis, only two had cirrhosis of the liver at post mortem examination. The 94 non-traumatic death subjects were divided into five categories by cause of death and whether fatty, liver was also present. The prevalence of decreased spermatogenesis was evaluated within each of these groups. It was not associated with any specific cause of death and only modestly with the presence or absence of a fatty liver (table 10).
198
KULLER, MAY AND PERPER TABLE 10
Relationship of cause of death and presence of fatty liver to prevalence of decreased spermatogenesis, Allegheny County, Pennsylvania, July 1,1974-December 1, 1975 Moderate to very severe decreased spermatogenesis
Fatty liver*
No.
No.
%
Atherosclerotic heart disease
Yes No
27 28
4 3
15 11
Fatty liver
Yes No
4
2
50
Other natural causes
Yes No
15 20
5 4
33 20
94
18
19
Cause of death
Total
• Fatty liver moderate to very severe. DISCUSSION
The results of this study suggest that alcohol consumption was related to decreased spermatogenesis. The testicular pathology was apparently independent of overt liver disease. Although quantification of alcohol consumption is extremely difficult, the majority of subjects with moderate to severe decreased spermatogenesis had consumed at least 417 gm of ethanol per week, an average of 32 drinks per week of whiskey, wine or beer. Five or six 12 oz bottles of beer per night is not an extremely unusual consumption pattern. Clearly, however, the relationship between dose, duration and intensity of consumption and testicular pathology, reduction of testosterone level, sterility, impotence and feminizatdon needs further evaluation. Mechanisms for decreased spermatogenesis and spermiogenesis as well as impotence and feminization have been suggested by several authors. The major question remains whether the changes in the testes are primary or secondary to liver disease. Moreover, the interesting hypothesis relating vitamin A and alcohol dehydrogenase to sterility proposed by Lester and Van Thiel (16) needs further evaluation in man.
The gross pathologic changes in the testes noted in this study were not associated in most cases with liver pathology. However, specific metabolic changes in the liver could occur without overt pathologic signs. The results of this study were consistent with the studies of Van Thiel, Lester (8, 9) and others suggesting a direct effect of alcohol on the testes. The epidemiology of impotence and sterility in man has not been adequately studied, as noted in a recent review article (19). Of particular interest may be the synergistic effect of alcohol and other drugs such as antihypertensive agents, as well as such diseases as diabetes and atherosclerosis, in the pathogenesis of impotence and. sterility. Also the relationship of alcohol consumption with other diseases could possibly be mediated by the effect of alcohol on testosterone concentration. The ratio of estrogen to testosterone may be related to the reported association of alcohol with lipoprotein distribution, risk of heart attack or certain cancers. REFERENCES
1. Van Thiel DH, Lester R: Progress in hepatology, alcoholism: Its effect on hypothalamic pituitary gonadal function. Gaatroenterology 71:318-327, 1976 2. Morrione TG: Effect of estrogens on the testis in hepatic insufficiency. Arch Pathol 37:39-48, 1944 3. Rather LJ: Hepatic cirrhosis and testicular atrophy. Arch Intern Med 80:397-402, 1947 4. Lloyd CW, Williams RH: Clinical studies: Endocrine changes associated with Laennec's cirrhosis of the liver. Am J Med 4:315-330, 1948 5. Bennett HS, Baggenstoas AH, Butt HR: The testis, breast and prostate of men who die of cirrhosis of the liver. Am J Clin Pathol 20:814-828, 1950 6. Galvao-Teles A, Burke CW, Anderson DC, et al: Biologically active androgens and estradiol in men with chronic liver disease. Lancet 1:173-177, 1973 7. Southren AL, Gordon GG, Olivo J, et aL Androgen metabolism in cirrhosis of the liver. Metabolism 22:695-702, 1973 8. Van Thiel DH, Sherins RJ, Lester R: Mechanism of hypogonadism in alcoholic liver disease. Gastroenterology 65:574, 1973 9. Van Thiel DH, Lester R, Sherins RJ: Hypogonadism in alcoholic liver disease: Evidence for a double defect. Gastroenterology 67:1188-1199, 1974 10. Van Thiel DH, Gavaler JS, Lester R, et al: Plasma estrone, prolactin neyrophysin, and sex steroidbinding globulin in chronic alcoholic men. Metab-
ALCOHOL, LIVER DISEASE, AND TESTICULAR PATHOLOGY olism 24:1015-1019, 1975 11. Kley HK, Nieschkg E, Wiegelmann W: Steroid hormones and their binding in plasma of male patients with fatty liver, chronic hepatitis and liver cirrhosis. Acta Endocrinol 79-^75-285, 1975 12. Huttunen MO, Harkonen M, Niskanen P, et al: Plasma testosterone concentration in alcoholics. J Stud Alcohol 37:1165-1177, 1976 13. Lemere F, Smith JW: Alcohol-induced sexual impotence. Am J Psychiatry 130:212-213, 1973 14. Ylikahri R, Huttunen M, Harkonen M, et a l Low plasma testosterone values in men during hangover. J Steroid Biochem 5:655-658, 1974 15. Gordon GG, Altaian K, Southren AL, et al: Effect of alcohol. (ethanol) administration on sex-hor-
16.
17.
18. 19.
199
mone metabolism in normal men. N Engl J Med 295:793-797, 1976 Van Thiel DH, Gavaler J, Lester R Ethanol inhibition of vitamin A metabolism in the testes: Possible mechanism for sterility in alcoholics. Science 186541-942, 1974 Van Thiel DH, Gavaler JS, Lester R, et al: Alcohol-induced testicular atrophy: An experimental model for hypogonadism occurring in chronic alcoholic men. Gastroenterology 69:326-332, 1975 Cahalan D, Room R: Problem Drinking among American Men. New Brunswick, NJ, Rutgers Center of Alcohol Studies, 1973 Levine SB: Marital sexual dysfunction: Erectile dysfunction. Ann Intern Med 85:342-350,1976
