Plasma Testosterone, Estradiol, and Gonadotrophins in Hepatic Insufficiency

Vol. 64, No.1

GASTROENTEROLOGY

Printed in U.S.A.

Copyright © 1973 by 'The Williams & Wilkins Co.

PLASMA TESTOSTERONE, ESTRADIOL, AND GONADOTROPHINS IN HEPATIC INSUFFICIENCY JOHN

R. KENT, M.D., REX J. SCARAMUZZI, PH.D., WALTER LAUWERS, F. PARLOW, PH.D., MELVIN HILL, RUTH PENARDI, AND

M.D.,

ALBERT

JESSAMINE HILLIARD, PH.D.

Long Beach Veterans Administration Hospital, Departments of Anatomy and Obstetrics and Gynecology, University of California at Los Angeles, and Department of Medicine, California College of Medicine, Irvine, California

The pituitary-gonadal axis was evaluated in 22 male patients with hepatic insufficiency, utilizing measurements of serum estradiol, testosterone (T), follicle-stimulating hormone, and luteinizing hormone. In these patients, only levels of T were significantly different from those obtained in normal men (3.9 ng per ml in patients versus 5.2 ng per ml in normal subjects, P < 0.05). Levels of follicle-stimulating hormone and luteinizing hormone were normal even in patients with markedly low serum T. In none of the patients with low serum T were gonadotrophins elevated to levels expected in primary testicular failure. The pathophysiology of hypogonadism in this disease may be more complicated than previous studies have indicated. levels of testosterone, estradiol, and gonadotrophins.

It is well known that patients with hepatic insufficiency may have low levels of circulating testosterone!' 2 and physical signs and symptoms of hypogonadism. 3 In men, these findings may include loss of libido, impotency, abnormal hair distribution, and testicular atrophy. Additionally, feminizing signs such as spider angiomata and gynecomastia may occur. Commonly cited to explain these findings is the hypothesis that circulating estrogen values are elevated because the liver is unable to inactivate steroids normally.3. 4 However, convincing support for this hypothesis has not been obtained as measurements of urinary estrogens, gonadotrophins, and estrogen clearance rates have been contradictory. The following study reinvestigates the role of the pituitary-gonadal axis in men with proved hepatic insufficiency, utilizing techniques which permit highly specific and sensitive assays for circulating

Patients and Methods Twenty-two men, ages 39 to 67, with histories of chronic alcoholism and hepatic insufficiency were studied. A diagnosis of liver insufficiency was established by clinical and biochemical findings, and in 9 cases, the diagnosis of hepatic cirrhosis was verified by percutaneous needle liver biopsy. In all cases, hepatomegaly was present and alcoholism was implicated as the principal etiological factor. Pertinent clinical information included, (a) the duration of excess alcohol consumption, (b) testicular sizemaximum diameter of the long axis measured by caliper with 4 cm considered the lower limit of normal! (c) spider angiomata, (d) gynecomastia, (e) ascites, (f) peripheral edema, and (g) varices. Hypogonadal symptoms such as impotency and generalized weakness were not included since these also may occur in patients with a variety of other chronic illnesses. It was the purpose of this study to correlate only objective signs and laboratory and clinical indices of hepatic dysfunction with the functional status of the pituitary-gonadal axis. Liver function tests routinely performed in

Received May 15, 1972. Accepted August 16, 1972. Address requests for reprints to: Dr. John R. Kent, Long Beach Veterans Administration Hospital, Long Beach, California 90801. 111

112

LIVER PHYSIOLOGY AND DISEASE

the Long Beach Veterans Administration Hospital included bilirubin (total and direct), serum albumin, serum alkaline phosphatase, and serum glutamic oxaloacetic transaminase. The methodology of the Technicon SMA 12/30 AutoAnalyzer was used. Bromosulphalein retention was studied in 5 patients and was elevated in each instance. Serum testosterone (T) was assayed by a double isotope technique. 5 Serum estradiol (E.-the method used did not allow separation of 17 ex and 17 (3), serum follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were determined by radioimmunoassays. 6-9 The lower limit of sensitivity of the FSH assay is 3 to 4 milli-international units (mIU) per m!. FSH and LH are expressed in terms of the Second International Reference Preparation of human menopausal gonadotropin. B. 9 Seven patients were restudied after 3 months of hospitalization during which time they abstained from alcohol. During hospitalization, dietary treatment was prescribed as indicated, including supplementary doses of B-complex vitamins. Hormonal studies in patients when initially hospitalized with liver insufficiency were compared with hormonal studies obtained in ageTABLE

Patient

Age

Testis size a

Left

Right

Vol. 64, No.1

matched healthy men. Serum estradiol was determined in an additional 6 patients with objective clinical and laboratory evidence of alcoholic hepatic insufficiency, since serum was available for this determination in only 6 of the original group.

Results Clinical. All patients admitted to a longstanding intake of ethanol but exact consumptions were difficult to determine because of the notorious unreliability of alcoholic individuals in estimating their intake. Esophageal varices were verified by esophagoscopy in 19 of the 22 patients; spider angiomata were present in 15, gynecomastia in 3; 4 had a bilateral decrease in testicular size and 4 others showed unilateral testicular atrophy. On admission, ascites was present in 12 patients and peripheral edema in 10 (table 1). Fifteen admitted to a decrease or loss of libido. Laboratory. Liver function was variable but abnormal in all of the 22 patients stud-

1. Clinical finding in hepatic insufficiency

Spider angioma

Gynecomastia

+ + + + +

-

-

-

-

-

-

-

-

-

-

-

-

+ + +

+

Ascites

Edema

Varices

Liver needle biopsy

cm

1 2 3 4 5 6 7 8 9 10 11

12 13 14 15 16 17 18 19 20 21 22 a

43 45 40 54 45 67 63 43 58 45 39 55 53 54 56 36 51 48 40 40 68 49

5.0 2.3 3.4 3.5 4.0 3.5 4.5 3.8 4.0 4.2 4.0 4.2 3.4 4.5 2.5 4.5 3.0 5.0 5.0

5.0 3.0 3.6 4.5 4.5 4.0 4.0 3.2 4.8 4.0 4.5 5.0 4.0 4.5 3.0 5.0 4.5 5.4 5.0

+ + + +

-

-

+ +

+ +

-

-

+ +

-

+ -

-

-

+ + +

-

-

-

-

+ +

-

+

+

-

-

-

+

-

-

-

-

+

+

+

-

-

-

-

-

+

-

-

-

+ +

+

+ + +

+ +

-

-

-

Normal testes diameter not less than 4 em.

-

+ -

+ + + + + + + +

N ondiagnostie Cirrhosis Cirrhosis Cirrhosis

-

Cirrhosis Cirrhosis

+ + + +

Cirrhosis Cirrhosis Nondiagnostie

-

+ + + + + +

Cirrhosis Cirrhosis

TABLE

Patient

Examination

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LIVER PHYSIOLOGY AND DISEASE

January 1973

2. Laboratory findings in hepatic insufficiency

Serum Alkaline a albumin a phosphatase

Bilirubin a Total

Direct

SGOT'

FSH'

LHd

mIU/ml serum

1

Initial Follow-up

2.1 25.3 2.8 1.4 31 18 37 2.2 16.5 0.6 36 23 27 1.7 2.7 3.0 2 11.5 1.6 37 5 12 Initial 3.5 14.1 3 1.0 95 2.0 Follow-up 3.4 2.0 1.0 61 10 13 4 0.4 52 3.1 9.2 1.8 7 5 4.5 29.6 1.2 0.6 125 4 12 0.4 17 13 6 2.9 14.4 0.6 9 Initial 7 3.7 32.0 1.1 0.6 48 10 8 Follow-up 3.7 31.0 1.0 0.4 32 8 11 Initial 8 1.8 14.0 6.6 3.9 240 12 18 Follow-up 3.6 9.5 0.5 45 23 1.0 9 3.3 23.7 10.2 6.1 20 177 Initial 1.2 27.0 32.0 22.0 10 20 840 3.9 15.0 3.5 1.6 16 26 Follow-up 11 Initial 4.0 32.3 7.9 2.6 135 <4 3.0 22.5 4.8 1.8 84 Follow-up 6 12 3.0 19.4 3.2 2.2 39 13 8 Initial 13 3.6 31.4 0.5 86 8 1.3 Follow-up 3.8 20.4 0.4 0.3 12 37 14 2.4 10.0 0.5 17 6 11 1.2 15 2.7 22.0 1.3 0.6 37 3 11 16 2.6 81 10 20.0 4.8 2.3 <3 17 3.9 21.5 0.6 0.3 13 12 25 18 4.9 12.1 0.8 0.2 22 6 11 19 4.3 0.8 10.3 0.3 17 37 20 2.7 0.3 24 13 14.4 0.5 7 21 2.8 12.3 1.8 0.5 14 19 97 22 4.5 9.0 1.0 0.5 14 27 <4 a Normal ranges: serum albumm, 3.5 to 5.0 g per 100 ml; serum alkalme phosphatase, 3 to strong units; bilirubin, total 0.15 to 1.0 mg per 100 ml, direct 0 to 0.2 mg per 100 ml. 'SGOT, serum glutamic oxaloacetic transaminase. Normal range, 10 to 50 mU per ml. FSH, follicle-stimulating hormone; mIU, mill i-international units. . d LH, luteinizing hormone. e T, testosterone. f E., serum estradiol.

T'

El

ng/ml

pg/ml

0.83 1.2 3.9 3.4 4.5 36 4.7 4.7 2.9 2.8 21 1.9 19 2.5 2.0 21 7.3 29 2.8 13 0.45 0.54 0.11 9 5.4 21 24 1.9 6.3 1.6 1.8 0.63 6.3 7.0 25 5.9 3.7 10.0 4.7 13 King-Arm-

C

ied (table 2). Improvement in some of the tests was noted in 5 of the 7 patients restudied after 3 months of hospitalization, and clinical improvement occurred in all 7. Mean ± SE serum testosterone of the patients was 3.9 ± 0.1 ng per ml, significantly lower (P < 0.05) than the mean of 5.2 ± 1.4 ng per ml in the 19 normal subjects. In 9 patients, T levels were below the range found by this laboratory in normal men (2.9 to 11.0 ng per ml), and in 3 patients the levels were within the range found in castrate males and normal fe-

males (0.43 to 1.60 ng per ml). There was no correlation between serum testosterone levels and any of the clinical assessments or laboratory indices of hepatic function evaluated (tables 1 and 2). Mean ± SE serum E2 of the 12 patients with hepatic insufficiency was 17.6 ± 2.0 pg per ml. The mean for the patients did not differ significantly from the values in 12 normal men (mean = 15.8 ± 2.2 pg per ml and range = 6 to 36 pg per ml). In the 5 patients with low T in whom E2 was also measured, the latter was in the normal

114

LIVER PHYSIOLOGY AND DISEASE

range (patients 7, 8, 10, 11, and 13). Levels of E2 in patients with hepatic insufficiency as well as those in normal men were considerably below those reported in normal women by Mishell and collaborators I 0 during the menstrual cycle. In normal women, these investigators reported mean E2 levels of 44, 78, and 112 pg per ml during the early follicular, late follicular, and midluteal phases of the menstrual cycle, respectively. In the patients, the mean ± SE serum FSH and LH levels were 10.1 ± 2.0 mIU per ml and 16.5 ± 1.7 mIU per ml, respectively. These levels for FSH and LH did not differ significantly from those found in 23 normal men (10.0 ± 0.9 and 14.3 ± 1.0 mIU per ml, respectively. The relationship of estrogen to gynecomastia cannot be properly assessed since E2 was not measured in any of the 3 patients with this disorder. Serum testosterone was low in 2 of these 3 patients and there was no consistent pattern of serum gonadotrophins. In the 5 patients with spider angioma in whom E2 was determined, levels were normal. Effect of therapy. Initial and follow-up studies in 7 of the patients after 3 months of hospitalization, revealed that despite clinical improvement in all and laboratory improvement in 5, serum testosterone and gonadotrophin levels were essentially unchanged (table 2).

Discussion The results of this study provide data to indicate that the pathophysiology of hypogonadism in men with alcoholic hepatic insufficiency may be more complicated than previous studies have suggested. Although most investigations have implicated secondary hypogonadism characterized by low urinary total gonadotrophins ll • 12 normal levels have also been reported. 13 In this study which utilized specific radioimmunoassays, plasma gonadotrophins were normal. Secondary hypogonadism has been reported in hemochromatosis. 14, 15 The results of this study in hepatic failure due to chronic alcoholism are not compatible with either simple primary or secondary hypo-

Vol. 64, No.1

gonadism; low levels of serum testosterone are associated with increased gonadotrophins in primary (testicular) hypogonadism and with decreased gonadotrophins in secondary (pituitary) hypogonadism. The low levels of T which persist despite normal levels of circulating gonadotrophins are suggestive of primary testicular failure. Assuming that the immunoassayable gonadotrophins are biologically active, it is difficult to avoid the conclusion that the testicular response to gonadotrophins is impaired. Certainly testicular atrophy is a common autopsy finding in patients with cirrhosis, but no relationship has been found between the severity of the hepatic failure and the degree of testicular atrophy. IS Explanations as to the mechanism underlying the postulated primary testicular failure can only be speculative. In some patients a component of secondary hypogonadism is also suggested by the failure of plasma gonadotrophins to rise significantly despite low T levels. Hypothalamic gonadotrophin-releasing factor(s) are important in maintaining normal pituitary secretion of gonadotrophins. 17 Disturbances of these releasing factors should be considered in hypotheses concerning the pathophysiology of abnormalities of the pituitary-gonadal axis in hepatic insufficiency. Increased amounts of bioassayable gonadotrophins have been extracted from pituitaries of patients who died of hepatic failure as compared with patients who had received estrogen treatment or who had died of other causes. 18 This previous finding as well as the impairment in gonadotrophin secretion suggested in this study could both be explained by a disorder of gonadotrophin releasing factor(s). Serum E 2 levels were normal in the 12 patients in whom these determinations were made. Previous studies, based upon urinary estrogen measurements, have been contradictory. Elevated 3, 12, 13 as well as normal 19 levels have been reported. While serum levels of other biologically active estrogens, such as estrone, are yet to be reported in hepatic failure, this study utilizing measurement of serum E2 does not support the concept of hyperestrogenism as an explanation for the low serum

Jaruw.ry 1973

LIVER PHYSIOLOG Y AND DISEASE

testosterone levels found in some patients with hepatic insufficiency. Similarly, elevated estradiol levels cannot explain the spider angiomata in patients with liver disease, since patients with these skin lesions, as well as those without, had similar estrogen levels. Much of the circulating T and E2 is bound to sex-steroid binding globulin(s). Recent studies suggest that it is the circulating unbound (free) forms of these steroids that are biologically active. 20. 21 Elevated levels of the sex-steroid binding globulin(s) have been reported in hepatic insufficiency. 22. 23 This elevation could result in a decreased percentage and quantity of unbound biologically active hormone which might not be reflected by measurement of total (bound plus free) T or E 2. Such was the conclusion in a recent report in which free testosterone was found to be disproportionately reduced compared with total testosterone. Testosteronebinding globulin was elevated and accounted for the discrepancy between the total and free testosterone levels. 20 REFERENCES 1. Coppage WS, Cooner AE: Testosterone in human

plasma. N Engl J Med 273:902-907, 1965 2. Young HH, Kent JR: Plasma testosterone levels in patients with prostatic carcinoma before and after treatment. J Urol 99:788-792, 1968 3. Lloyd CW, Williams RH: Endocrine changes associated with Laennec's cirrhosis of liver. Am J Med 4:315-330, 1948 4. Glass SF, Edmondson HA: Sex hormone changes associated with liver disease. Endocrinology 27: 749-752, 1940 5. Kent JR, Acone AB: Plasma testosterone levels and aging in males, Androgens in Normal and Pathological Conditions. Edited by A Vermeulen, D Exley. New York, Proceedings of the Second Symposium on Steroid Hormones, Internat Congress Series 101, Excerpta Med Foundation, 1966, p 31-35 6. Hotchkiss J, Atkinson LE, Knobil E: Time course of serum estrogen and luteinizing hormone (LH) concentrations during the menstrual cycle of the Rhesus monkey. Endocrinology 89 :177-183, 1971 7. Scaramuzzi RJ, Hilliard J: Effects of FSH on ovarian estrogen secretion in rabbits (abstract 197) . Program of the 53rd Meeting, The Endocrine Society, 1971, p A 141

115

8. Odell WO, Parlow AF, Cargille CM, et al: Radioimmunoassay for human follicle-stimulating hormone: physiological studies. J Clin Invest 47 : 2551-2562, 1968 9. Schalch DS, Parlow AF, Boon RC, et al: Measurement of human leuteinizing hormone in plasma by radioimmunoassay. J Clin Invest 47:665-678, 1968 10. Mishell DR Jr, Nakamura RM, Crosingnani PG, et al: Serum gonadotropin and steroid patterns during the normal menstrual cycle. Am J Obstet Gynecol 111:60-65, 1971 11. Pincus IJ, Rakoff AE, Cohn EM, et al: Hormonal studies in patients with chronic liver disease. Gastroenterology 19:735-754, 1951 12. Dohan FC, Richardson EM, Bluemle LW Jr, et al : Hormone excretion in liver disease. J Clin Invest 31:481-498, 1952 13. Rupp J, Cantarow A, Rakoff AE, et al: Hormone excretion in liver disease and gynecomastia. J Clin Endocrinol Metab 11:688-699, 1951 14. Kent JR, Aronow WS, Meister L: Hypogonadotrophic hypogonadism in haemochromatosis. Calif Med 111:450-452, 1969 15. Stocks AE, Martin FIR: Pituitary function in hemochromatosis. Am J Med 45:839-845, 1968 16. Bennet HS, Baggenstoss AH, Butt HR: Testis, breast and prostate of men who die of cirrhosis of liver. Am J Clin Pathol 20:814-828, 1950 17. Frohman LA: Clinical neuropharmacology of hypothalamic releasing factors. N Engl J Med 286: 1391-1397, 1972 18. Russfield AB, Sommers SC: The effect of cirrhosis of the liver on gonadotropin content of the human hypophysis (abstr) . Fed Proc 19:156, 1960 19. Cameron CB: Urinary excretion of oestrone, oestradiol-17 ~ and oestriol in patients with chronic liver damage. J Endocrinol 15:199-205, 1957 20. Vermeulen A, Rubens R, Verdonck L: Testosterone secretion and metabolism in male senescence. J Clin Endocrinol 34:730-735, 1972 21. Mauvais Jarvais P, Crepy 0, Bercovici JP : Further studies on the pathophysiology of testicular feminization syndrome. J Clin EndocrinoI 32: 568571, 1971 22. Breuer Von J, Schneider HTh, Breuer H: Comparative studies on the binding of testosterone and 17 ~-oestradiol by serum proteins in normals and in patients with liver cirrhosis, Research on Steroids, vol 4. Edited by M Finkelstein, A Klopper, C Conti, et al. Oxford, New York, Permagon Press, 1970, p 109-115 23. Tavernetti RR, Rosenbaum W, Kelly WG, et al: Evidence for the presence in human plasma of an estrogen-binding factor other than albumin : abnormal binding of estradiol in men with hepatic cirrhosis. J Clin Endocrinol 27:920-926, 1967

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GASTROENTEROLOGY

Copyright © 197:3 by The Williams & Wilkins Co.

CASE REPORTS CEREBRAL VENOUS THROMBOSIS IN ULCERATIVE COLITIS IVAN T. BORDA, M.D., F.R.C.P.(C), ROBERT F. SOUTHERN, M.D., AND WILLIAM F. BROWN, M.D., F.R.C.P.(C) Department of Medicine, St. Joseph's Hospital, University of Western Ontario, London, Canada

A case of massive cerebral and generalized venous thrombosis occurring in a young man with ulcerative colitis is reported. This association appears to be rare; only 2 cases have been previously reported. The literature on thromboembolic complications and coagulation abnormalities in ulcerative colitis is reviewed. Thromboembolic phenomena are not frequently recognized clinically but the incidence is higher in autopsy studies. Thromboembolic disease is a significant complication of ulcerative colitis. Reports on this subject generally fail to specify the sites of thromboembolism; the pelvic plexus, lungs, spleen, and kidneys are mentioned. I - 6 Acute thrombophlebitis of the thoracoepigastric vein (Mondor's disease) has been reported. 7 In 1967, Harrison and Truelove 8 described 2 patients with ulcerative colitis who developed cerebral venous thrombosis. This appears to be the only detailed report of such an association. We have observed a young man with ulcerative colitis who developed rapid and fatal intracranial venous thrombosis.

Case Report A 23-year-old male was admitted with a 3month history of diarrhea which became bloody 2 weeks before admission. Past history was irrelevant, physical examination negative. An elder sister had ulcerative colitis since age 13. Sigmoidoscopy and rectal biopsy showed ulcerReceived February 17, 1972. Accepted September

11, 1972,

Address requests for reprints to: Dr. Ivan T. Borda, St. Joseph's Hospital, London, Ontario, Canada. The authors acknowledge the help of Dr. Katherine L. Turner in describing the autopsy findings. 116

ative proctitis. Barium enema was normal. Hemogram, urinalysis, blood urea nitrogen, LFT's, stool cultures, and electrolytes were normal. He was treated with Salazopyrine and steroid enemas with marked remission which continued for 6 months. He was readmitted on June 25th, 1971, with bloody diarrhea again. Repeat sigmoidoscopy showed a fiery red, bleeding velvety mucosa, but no gross ulceration. A repeat barium enema was normal. Hemoglobin was 10.4 g per 100 ml, erythrocyte sedimentation rate 54 mm per hr. He had a white count of 1,400 per mm 3 with a neutropenia. Platelet count was 173,000 per mm 3. Serum iron, iron binding capacity, haptoglobin, red cell folate levels, serum B12 levels, osmotic fragility, and hemoglobin electrophoresis were normal. One G.6.P.D. was low at 456 international units per ml. Direct Coomb's test was negative. Bone marrow examination revealed a maturation arrest of the granulocytic series with megaloblastic hyperplasia of the erythroid series. Urinalysis, stool culture, blood sugars, blood urea nitrogen, creatinine, creatinine clearance, glucose tolerance test, serum calcium, phosphorus, and protein electrophoresis were all within normal limits. Serum uric acid was 7.7 mg per 100 ml (normal 2.5 to 6.0). Salazopyrine was discontinued and he was treated with steroid enemas and a low residue diet. Both his hematological picture and his bowel symptoms showed marked improvement over the next 2 weeks. A third barium enema, upper gastrointestinal series, and small bowel