Olinical Investigator
Clin Investig (1992) 70:566-572
Original ArticEe
© Springer-Verlag 1992
Testosterone treatment of men with idiopathic hemochromatosis H.K. Kley 1, W. Stremmel 2, J.B. Kley 2, and R. Schlaghecke 2 1 Stfidtisches Krankenhaus, Singen/Hohentwiel 2 Medizinische Klinik C und D der Heinrich-Heine-Universit/it, Dfisseldorf
Summary. Patients with chronic liver disease usually exhibit low plasma levels of testosterone with loss of libido and potency; this is also valid in male patients suffering from idiopathic hemochromatosis (IHC), in whom nowadays the diagnosis is made at an earlier age. Therefore, the effect of testosterone treatment was studied in 10 patients with IHC. After the application of 250 mg testosterone enanthate i.m., the plasma testosterone (from 2.4_+1.9 to 20.1_7.4ng/ml) and estradiol (from 17.4+6.3 to 38.5+14.2pg/ml) levels increased significantly. The rise of estradiol was in the range of controls and smaller than reported in other chronic liver diseases. In a long-term study, 250 mg testosterone enanthate was given 4weekly for 33-96 months to 5 patients with IHC. General well-being, libido, and potency recovered almost immediately. Over a treatment period of 27.3 patient years, symptoms of hyperestrogenism (gynecomastia) or (portal vein) thrombosis were not seen, both of which had been described in patients with alcoholic liver cirrhosis. There was no deterioration of liver function. The effect of testosterone treatment on the patients' well-being and plasma hormone concentrations remained unchanged over the whole period of testosterone treatment. Thus, in male patients with IHC and lowered plasma testosterone, treatment with testosterone enanthate may be instituted. Because of the positive effects on general well-being, liver regeneration capacity, and potency, testosterone should especially be administered to younger subjects suffering from IHC. Key words: Idiopathic hemochromatosis - Testosterone treatment - Plasma testosterone - Plasma estradiol - Sexual hormone binding globulin
Gonadal dysfunction with a lowered testosterone concentration is a common manifestation of Abbreviations: IHC =idiopathic hemochromatosis; LH = luteinizing hormone; SHBG = sexual hormone binding globulin
chronic liver diseases including idiopathic hemochromatosis (IHC) [6, 14, 26]. According to several studies previously reviewed [5], treatment with testosterone may influence beneficially the course and prognosis of patients with alcoholic cirrhosis [25]. However, side-effects of this treatment relevant to both metabolic and clinical findings have to be expected, since increased estrogen formation and elevated estrogenic effects have been shown to occur [2, 16]. In patients with IHC, however, the conversion of androgens to estrogens was found to be normal [19] and consequently, the gynecomastia usually seen in patients with alcoholic liver cirrhosis was not found [23]. Therefore, we investigated whether or not testosterone may be given to patients with IHC. This may be essential, since nowadays the diagnosis of IHC is usually made when patients are young [23] and suffer from hypogonadism and impaired potency. Furthermore, osteoporosis due to androgen deficiency has been described in IHC [4, 8, 28], but life expectancy is normal when therapy is performed adequately [23]. First, we studied the effect of one injection of 250 mg testosterone enanthate on plasma androgen and estrogen levels in patients with IHC. Thereafter, a long-term study was instituted in 5 patients with IHC with 4-weekly injections over a period of 33-96 months. Methods
Subjects Ten male patients with IHC were studied before they underwent venesection therapy. Initially, phlebotomy was performed with the removal of 500 ml of blood twice a week down to a hemoglobin concentration of 10 g/dl; thereafter, the hemoglobin level was maintained between 10 and 12 g/ dl. Diagnosis was confirmed by clinical profile, laboratory tests, and liver biopsy (Table 1). On histological examination, 6 patients showed hepatic fibrosis and 4 hepatic cirrhosis. Alcohol consumption was normal ( < 2 0 g/die) except in patient
567 Table 1. Clinical profiles of patients suffering from idiopathic hemochromatosis (IHC) before testosterone treatment. Patients' weight was between 95% and 120% of ideal body weight No.
1
2 3 4 5 6 7 8 9 10
Age (years)
42 42 34 49 28 45 49 48 48 39
Weight/height (kg/cm)
83 q78 66 q65 68 /165 75 q 80 75 /175 78 /178 75 /179 76 /177 85 /180 66 /168
Diabetes
0 + 0 + + + (+) (+) (+) 0
Liver Size" (cm)
Histology result
16 10 15 14 14 13 14 14 11 12
Fi Ci Ci Ci Ci Fi Fi Fi Fi Fi
Testes (ml)
Libido
Potency b
Duration of symptoms (years)
14 12 6 10 14 22 16 19 19 20
0 0 0 0 0 0 n -
1 0 0 0 1 1 0 4 1 2
2 4 7 1 2 4 1 0 5 2
( + ) = p a t h o l o g i c glucose tolerance test; F i = fibrosis of the liver; Ci=cirrhosis of the liver; Libido (as judged by the patient): - = decreased; n = normal a Liver size in the medioclavicular line (cm) b Potency = frequency of sexual intercourse per m o n t h
no. 4, who had drunk 75 g alcohol/die over a period of 2 years. To exclude the interference of other endocrine alterations due to advanced age [13] or obesity [17], only patients younger than 50 years of age and with a body weight less than 130% of the ideal (Metropolitan Life Insurance Co. tables) participated in the study. For comparison, 10 age-matched ( _ 3 years) healthy men were studied. Informed written consent was obtained from each subject. The study protocol was approved by the local ethics committee.
Study protocol In the "short-term study" testosterone enanthate (Testoviron-Depot 250 rag, Schering, Germany) was given i.m. [12] to 10 patients before phlebotomy therapy was initiated. Thereafter, in the "long-term study" 250 mg testosterone enanthate was injected 4-weekly over a period of 33-96 months. As we insisted on checking the patients' health regularly at the university (once a month), only 5 patients were included in the long-term study. Blood was taken before the testosterone application and on days 1, 2, 4, 7, 10, 14, 17, 21, 24, and 28. In the long-term study this was done every 6 months. Ultrasonography of the liver and the usual laboratory analysis were performed monthly to half-yearly.
Hormone analysis Basal levels of testosterone, androstenedione, estrone, and estradiol were measured in 3 plasma
samples, which were taken at 20-min intervals between 8 and 9 a.m. The heparinized blood was centrifuged, and the plasma was frozen at - 2 8 ° C until analysis. Steroids were analyzed by radioimmunoassay after chromatographic purification using specific antibodies [18]. Recovery was 7 0 % 90%, sensitivity was 5-15 pg per tube, and interassay variation was 3%-10%. LH (luteinizing hormone) and SHBG (sex hormone binding globulin) were measured using a commercially available kit (IDW, Frankfurt, Germany). The usual laboratory analyses (serum albumin, alkaline phosphatase, coagulation, blood count, and liver enzymes) were done in the laboratories of the university.
Statistics Results are given as mean + SD. Unless otherwise stated, statistical analysis was performed with Student's t-test. Results
Five of 10 patients with IHC had decreased libido 1-7 years before the diagnosis of IHC was made (Table 1); a complete loss of libido was present in 6 patients. Impotence was claimed by 4 patients with IHC and decreased sexual performance by 5. Testes were decreased in size ( < 2 0 ml) in all but 1 patient. Feminization (gynecomastia) was not found. None had ascites or intestinal bleeding. The liver was larger than 12 cm in the medioclavicular line in 6 patients. There were no signs of decreased hepatic synthesizing capacity; serum albumin (34-46 g/l) and coagulation tests were nor-
568 Table 2. Hormone concentrations basal values) in patients with IHC and healthy, age-matched controls No.
Testosterone (ng/ml)
Androstenedione (ng/ml)
Estradiol (pg/ml)
Estrone (pg/ml)
LH (U/I)
SHBG (nmol/1)
1 2 3 4 5 6 7 8 9 10
2.07 0.39 0.15 0.48 1.72 3.54 1.49 4.97 4.15 5.06
0.75 0.33 0.41 0.49 0.69 0.79 0.55 0.96 0.94 1.20
17.0 16.0 7.0 10.0 18.0 21.8 14.0 27.0 22.8 23.7
33.0 28.0 28.5 30.0 28.0 29.7 26.0 29.0 36.8 28.5
5.0 7.9 4.2 6.3 6.7 5.9 5.0 7.9 3.7 9.0
40.7 44.7 39.5 54.1 43.5 29.4 56.0 18.4 26.0 33.0
~___ SD
2.40 1.89
0.72 0.28
17.7 6.3
29.8 3.1
6.2 1.7
38.5 12.0
Controls (n = 10): 2± SD
7.71 1.60
0.82 0.21
28.5 8.5
32.5 5.6
10.1 2.8
27.2 8.3
P
Clin Investig (1992) 70:566-572
Original ArticEe
© Springer-Verlag 1992
Testosterone treatment of men with idiopathic hemochromatosis H.K. Kley 1, W. Stremmel 2, J.B. Kley 2, and R. Schlaghecke 2 1 Stfidtisches Krankenhaus, Singen/Hohentwiel 2 Medizinische Klinik C und D der Heinrich-Heine-Universit/it, Dfisseldorf
Summary. Patients with chronic liver disease usually exhibit low plasma levels of testosterone with loss of libido and potency; this is also valid in male patients suffering from idiopathic hemochromatosis (IHC), in whom nowadays the diagnosis is made at an earlier age. Therefore, the effect of testosterone treatment was studied in 10 patients with IHC. After the application of 250 mg testosterone enanthate i.m., the plasma testosterone (from 2.4_+1.9 to 20.1_7.4ng/ml) and estradiol (from 17.4+6.3 to 38.5+14.2pg/ml) levels increased significantly. The rise of estradiol was in the range of controls and smaller than reported in other chronic liver diseases. In a long-term study, 250 mg testosterone enanthate was given 4weekly for 33-96 months to 5 patients with IHC. General well-being, libido, and potency recovered almost immediately. Over a treatment period of 27.3 patient years, symptoms of hyperestrogenism (gynecomastia) or (portal vein) thrombosis were not seen, both of which had been described in patients with alcoholic liver cirrhosis. There was no deterioration of liver function. The effect of testosterone treatment on the patients' well-being and plasma hormone concentrations remained unchanged over the whole period of testosterone treatment. Thus, in male patients with IHC and lowered plasma testosterone, treatment with testosterone enanthate may be instituted. Because of the positive effects on general well-being, liver regeneration capacity, and potency, testosterone should especially be administered to younger subjects suffering from IHC. Key words: Idiopathic hemochromatosis - Testosterone treatment - Plasma testosterone - Plasma estradiol - Sexual hormone binding globulin
Gonadal dysfunction with a lowered testosterone concentration is a common manifestation of Abbreviations: IHC =idiopathic hemochromatosis; LH = luteinizing hormone; SHBG = sexual hormone binding globulin
chronic liver diseases including idiopathic hemochromatosis (IHC) [6, 14, 26]. According to several studies previously reviewed [5], treatment with testosterone may influence beneficially the course and prognosis of patients with alcoholic cirrhosis [25]. However, side-effects of this treatment relevant to both metabolic and clinical findings have to be expected, since increased estrogen formation and elevated estrogenic effects have been shown to occur [2, 16]. In patients with IHC, however, the conversion of androgens to estrogens was found to be normal [19] and consequently, the gynecomastia usually seen in patients with alcoholic liver cirrhosis was not found [23]. Therefore, we investigated whether or not testosterone may be given to patients with IHC. This may be essential, since nowadays the diagnosis of IHC is usually made when patients are young [23] and suffer from hypogonadism and impaired potency. Furthermore, osteoporosis due to androgen deficiency has been described in IHC [4, 8, 28], but life expectancy is normal when therapy is performed adequately [23]. First, we studied the effect of one injection of 250 mg testosterone enanthate on plasma androgen and estrogen levels in patients with IHC. Thereafter, a long-term study was instituted in 5 patients with IHC with 4-weekly injections over a period of 33-96 months. Methods
Subjects Ten male patients with IHC were studied before they underwent venesection therapy. Initially, phlebotomy was performed with the removal of 500 ml of blood twice a week down to a hemoglobin concentration of 10 g/dl; thereafter, the hemoglobin level was maintained between 10 and 12 g/ dl. Diagnosis was confirmed by clinical profile, laboratory tests, and liver biopsy (Table 1). On histological examination, 6 patients showed hepatic fibrosis and 4 hepatic cirrhosis. Alcohol consumption was normal ( < 2 0 g/die) except in patient
567 Table 1. Clinical profiles of patients suffering from idiopathic hemochromatosis (IHC) before testosterone treatment. Patients' weight was between 95% and 120% of ideal body weight No.
1
2 3 4 5 6 7 8 9 10
Age (years)
42 42 34 49 28 45 49 48 48 39
Weight/height (kg/cm)
83 q78 66 q65 68 /165 75 q 80 75 /175 78 /178 75 /179 76 /177 85 /180 66 /168
Diabetes
0 + 0 + + + (+) (+) (+) 0
Liver Size" (cm)
Histology result
16 10 15 14 14 13 14 14 11 12
Fi Ci Ci Ci Ci Fi Fi Fi Fi Fi
Testes (ml)
Libido
Potency b
Duration of symptoms (years)
14 12 6 10 14 22 16 19 19 20
0 0 0 0 0 0 n -
1 0 0 0 1 1 0 4 1 2
2 4 7 1 2 4 1 0 5 2
( + ) = p a t h o l o g i c glucose tolerance test; F i = fibrosis of the liver; Ci=cirrhosis of the liver; Libido (as judged by the patient): - = decreased; n = normal a Liver size in the medioclavicular line (cm) b Potency = frequency of sexual intercourse per m o n t h
no. 4, who had drunk 75 g alcohol/die over a period of 2 years. To exclude the interference of other endocrine alterations due to advanced age [13] or obesity [17], only patients younger than 50 years of age and with a body weight less than 130% of the ideal (Metropolitan Life Insurance Co. tables) participated in the study. For comparison, 10 age-matched ( _ 3 years) healthy men were studied. Informed written consent was obtained from each subject. The study protocol was approved by the local ethics committee.
Study protocol In the "short-term study" testosterone enanthate (Testoviron-Depot 250 rag, Schering, Germany) was given i.m. [12] to 10 patients before phlebotomy therapy was initiated. Thereafter, in the "long-term study" 250 mg testosterone enanthate was injected 4-weekly over a period of 33-96 months. As we insisted on checking the patients' health regularly at the university (once a month), only 5 patients were included in the long-term study. Blood was taken before the testosterone application and on days 1, 2, 4, 7, 10, 14, 17, 21, 24, and 28. In the long-term study this was done every 6 months. Ultrasonography of the liver and the usual laboratory analysis were performed monthly to half-yearly.
Hormone analysis Basal levels of testosterone, androstenedione, estrone, and estradiol were measured in 3 plasma
samples, which were taken at 20-min intervals between 8 and 9 a.m. The heparinized blood was centrifuged, and the plasma was frozen at - 2 8 ° C until analysis. Steroids were analyzed by radioimmunoassay after chromatographic purification using specific antibodies [18]. Recovery was 7 0 % 90%, sensitivity was 5-15 pg per tube, and interassay variation was 3%-10%. LH (luteinizing hormone) and SHBG (sex hormone binding globulin) were measured using a commercially available kit (IDW, Frankfurt, Germany). The usual laboratory analyses (serum albumin, alkaline phosphatase, coagulation, blood count, and liver enzymes) were done in the laboratories of the university.
Statistics Results are given as mean + SD. Unless otherwise stated, statistical analysis was performed with Student's t-test. Results
Five of 10 patients with IHC had decreased libido 1-7 years before the diagnosis of IHC was made (Table 1); a complete loss of libido was present in 6 patients. Impotence was claimed by 4 patients with IHC and decreased sexual performance by 5. Testes were decreased in size ( < 2 0 ml) in all but 1 patient. Feminization (gynecomastia) was not found. None had ascites or intestinal bleeding. The liver was larger than 12 cm in the medioclavicular line in 6 patients. There were no signs of decreased hepatic synthesizing capacity; serum albumin (34-46 g/l) and coagulation tests were nor-
568 Table 2. Hormone concentrations basal values) in patients with IHC and healthy, age-matched controls No.
Testosterone (ng/ml)
Androstenedione (ng/ml)
Estradiol (pg/ml)
Estrone (pg/ml)
LH (U/I)
SHBG (nmol/1)
1 2 3 4 5 6 7 8 9 10
2.07 0.39 0.15 0.48 1.72 3.54 1.49 4.97 4.15 5.06
0.75 0.33 0.41 0.49 0.69 0.79 0.55 0.96 0.94 1.20
17.0 16.0 7.0 10.0 18.0 21.8 14.0 27.0 22.8 23.7
33.0 28.0 28.5 30.0 28.0 29.7 26.0 29.0 36.8 28.5
5.0 7.9 4.2 6.3 6.7 5.9 5.0 7.9 3.7 9.0
40.7 44.7 39.5 54.1 43.5 29.4 56.0 18.4 26.0 33.0
~___ SD
2.40 1.89
0.72 0.28
17.7 6.3
29.8 3.1
6.2 1.7
38.5 12.0
Controls (n = 10): 2± SD
7.71 1.60
0.82 0.21
28.5 8.5
32.5 5.6
10.1 2.8
27.2 8.3
P
