A Study of Pituitary Function in Patients with Idiopathic Hemochromatosis C. H. WALSH, A. D. WRIGHT, J. W. WILLIAMS, AND G. HOLDER General Hospital, Birmingham University Medical School, and Women's Hospital, England
Birmingham,
ABSTRACT. Pituitary function was assessed in twelve male patients with idiopathic hemochromatosis. Though clinical features suggestive of hypogonadism were noted in nine cases, impaired pituitary function was demonstrated in only two instances. Our findings suggest that factors other
than pituitary or testicular failure contribute significantly to the occurrence of sexual hypofunction and other features suggestive of hypogonadism seen in many of these patients. (J Clin Endocrinol Metab 43: 866, 1976)
ALTHAUSEN (1) and Sheldon (2) both
from 46 to 72 years (mean 58 years). The diagnosis of hemochromatosis was based on the finding of typical clinical features together with a serum iron of at least 230 jug/100 ml and a saturated iron binding capacity of 75% or more. In addition, the diagnosis was confirmed by liver biopsy in eight of the cases. In three patients, the diagnosis of hemochromatosis had been made less than a month prior to investigation of their endocrine status. In the remaining patients, the diagnosis of hemochromatosis had been made from 4-20 years previously (Table 1). All patients had had venesections at various times; the total amount of blood removed in individual cases varying from 2-110 litres. In two patients, liver function tests were mildly abnormal at the time of this study. Ten of the twelve patients suffered from diabetes mellitus. Seven were being treated with insulin in doses varying from 24 to 88 units daily. In three patients, diabetes was controlled by oral hypoglycemic agents. The remaining two patients had normal oral glucose tolerance tests. All patients had a detailed physical examination. Distribution of body hair, the presence of gynecomastia and testicular size were all assessed clinically. Testicular atrophy was considered to be present when the testes measured less than 2.5 cm x 3.0 cm. Gynecomastia was assessed clinically as being "slight" or "marked." A full history of sexual function was recorded, and libido and potency were assessed subjectively. A modified combined pituitary function test (8) was carried out on all patients. In ten cases this commenced at 0900 h after an overnight fast. In two cases the test was commenced at 1400 h after a four h fast. Each patient received by iv injection LHRH 100 jug (Hoechst), TRH 200 ng, and porcine insulin
i l
emphasized the importance of hypo-
gonadism as a feature of hemochromatosis. Subsequent reports have suggested that hypogonadism may occur in 50-80% of patients (3,4). It is only in recent years that the nature of this problem has been investigated and so far general agreement has not been reached. Finch and Finch (5) found that the features of hypogonadism were closely related to the severity of the liver damage, indicating that the mechanism was the same as for the hypogonadism found in association with other forms of liver disease. The study of Stocks and Martin (3) does not support this view. These investigators postulated that hypogonadism was associated with pituitary failure, which they assumed was the result of iron deposition. Similar findings have been recorded by others (6,7). In contrast, however, Simon et al. (4) found a poor correlation between pituitary function and clinical features of hypogonadism, and they suggested that the predominant lesion was more likely to be in the testes rather than in the pituitary. In order to investigate this problem further, we have carried out a comprehensive study of pituitary function in a non-selected group of patients with idiopathic hemochromatosis. Materials and Methods Twelve male patients with idiopathic hemochromatosis were investigated. Their ages ranged Received December 22, 1975.
866
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 18 December 2014. at 06:45 For personal use only. No other uses without permission. . All rights reserved.
867
PITUITARY IN HEMOCHROMATOSIS (Actrapid) in doses varying from 0.2 U-0.5 U/kg BW. Blood samples were taken in the basal state for measurement of testosterone, sex hormone binding globulin capacity (SHBGC), luteinizing hormone (LH), follicle stimulating hormone (FSH), thyrotrophic hormone (TSH), human growth hormone (GH) and cortisol. Further samples were withdrawn at thirty and sixty min for all of these measurements with the exception of testosterone and SHBGC. In addition samples were withdrawn at ninety min for HGH and cortisol. On a subsequent occasion basal samples were taken for measurement of serum prolactin in ten patients. Serum LH and FSH were measured by specific double antibody radioimmunoassay (9). Results were expressed as U/L of M.R.C. Human Pituitary Standard (69/104). GH was measured by double antibody radioimmunoassay (W.H.O. First I.R.P.). Likewise serum TSH was measured by double antibody radioimmunoassay and the results expressed in mU/L of M.R.C. Human Pituitary Standard (68/38). Serum testosterone was measured by radioimmunoassay (10) using antibodies raised as described by Erlanger et al. (11). Serum extracts were purified by two stage thin layer chromatography prior to assay. SHBGC was measured by the method of Rudd et al. (12). Serum prolactin was measured as described by Glass et al. (13), but using NIH V-L-S 2 for iodination. Serum cortisol was measured by the technique of competitive protein binding (14).
Results In nine of the twelve patients features suggestive of hypogonadism were observed. In two of these cases the features were marked, in five cases only mild features were noted, while in the other two cases the only features possibly attributable to hypogonadism were subjective (reduced libido and impotence); (Table 2). The most common objective feature suggestive of hypogonadism was reduced body hair. This was seen in five patients and was charTABLE 2.
TABLE 1. Details of 12 patients with hemochromatosis (10 diabetics) Years
Known duration of hemochromatosis Known duration of diabetes
15
6
3
2
1
2
3
2
3
acterized by an absence of chest hair, reduced axillary hair, and female distribution of pubic hair. In all cases it was of gradual onset and not attributable to racial or genetic factors. Gynecomastia was of slight degree in both patients in whom it occurred. Neither patient was taking any drugs known to stimulate breast tissue. Assessment of the subjective features of hypogonadism (loss of libido and impotence) is a particularly difficult problem, especially in patients in the older age group. However, when compared to a control group of healthy subjects, libido was deemed to be reduced in seven instances. Impotence was total in the four patients in whom it occurred. Figure 1 shows the basal testosterone values for ten patients in whom the measurements were made. In two cases the values were below the normal range. In both instances sex hormone binding capacity was normal. Sex hormone binding capacity was also normal in all of the other cases. Likewise, serum prolactin levels were within the normal range in all patients in whom the measurements were made. Figure 2 shows the mean results for LH and FSH. Also shown are the mean values in a control group of ten diabetics who were potent and who did not have hemochromatosis. The age range of the control group was 30 to 65 years (mean 41 years). The mean values for the patients with hemochromatosis are within the normal
Details of clinical features of hypogonadism
Libido
Impotent
Testicular atrophy
Body hair
Gynecomastia
7
4
3
5
2
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 18 December 2014. at 06:45 For personal use only. No other uses without permission. . All rights reserved.
868
JCE & M • 1976 V'ol 43 • No 4
WALSH ETAL.
60 .
50 .
values did not increase in two of these four patients, while in all four cases serum cortisol levels rose only marginally, or not at all. In all cases, however, the basal cortisol values were within the normal range. Discussion
§
40 J
O
30 .
o E c
Q£
UJ HO hto
20 .
10 .
10 PATIENTS WITH HAEMOCHROMATOSIS FIG. 1. Basal testosterone levels in 10 patients.
range, and do not differ significantly from the values for the control group (P > .05). On an individual basis, however, both the LH and FSH responses to LHRH were abnormally low in two patients with hemochromatosis. Both of these patients had low serum testosterone levels. The overall response to TRH was normal (Table 3). However in one patient TSH failed to rise. This patient had also failed to respond to LHRH. The growth hormone and cortisol responses to IV insulin are shown in Figs. 3 and 4. It should be noted that hypoglycemia (blood sugar
Birmingham,
ABSTRACT. Pituitary function was assessed in twelve male patients with idiopathic hemochromatosis. Though clinical features suggestive of hypogonadism were noted in nine cases, impaired pituitary function was demonstrated in only two instances. Our findings suggest that factors other
than pituitary or testicular failure contribute significantly to the occurrence of sexual hypofunction and other features suggestive of hypogonadism seen in many of these patients. (J Clin Endocrinol Metab 43: 866, 1976)
ALTHAUSEN (1) and Sheldon (2) both
from 46 to 72 years (mean 58 years). The diagnosis of hemochromatosis was based on the finding of typical clinical features together with a serum iron of at least 230 jug/100 ml and a saturated iron binding capacity of 75% or more. In addition, the diagnosis was confirmed by liver biopsy in eight of the cases. In three patients, the diagnosis of hemochromatosis had been made less than a month prior to investigation of their endocrine status. In the remaining patients, the diagnosis of hemochromatosis had been made from 4-20 years previously (Table 1). All patients had had venesections at various times; the total amount of blood removed in individual cases varying from 2-110 litres. In two patients, liver function tests were mildly abnormal at the time of this study. Ten of the twelve patients suffered from diabetes mellitus. Seven were being treated with insulin in doses varying from 24 to 88 units daily. In three patients, diabetes was controlled by oral hypoglycemic agents. The remaining two patients had normal oral glucose tolerance tests. All patients had a detailed physical examination. Distribution of body hair, the presence of gynecomastia and testicular size were all assessed clinically. Testicular atrophy was considered to be present when the testes measured less than 2.5 cm x 3.0 cm. Gynecomastia was assessed clinically as being "slight" or "marked." A full history of sexual function was recorded, and libido and potency were assessed subjectively. A modified combined pituitary function test (8) was carried out on all patients. In ten cases this commenced at 0900 h after an overnight fast. In two cases the test was commenced at 1400 h after a four h fast. Each patient received by iv injection LHRH 100 jug (Hoechst), TRH 200 ng, and porcine insulin
i l
emphasized the importance of hypo-
gonadism as a feature of hemochromatosis. Subsequent reports have suggested that hypogonadism may occur in 50-80% of patients (3,4). It is only in recent years that the nature of this problem has been investigated and so far general agreement has not been reached. Finch and Finch (5) found that the features of hypogonadism were closely related to the severity of the liver damage, indicating that the mechanism was the same as for the hypogonadism found in association with other forms of liver disease. The study of Stocks and Martin (3) does not support this view. These investigators postulated that hypogonadism was associated with pituitary failure, which they assumed was the result of iron deposition. Similar findings have been recorded by others (6,7). In contrast, however, Simon et al. (4) found a poor correlation between pituitary function and clinical features of hypogonadism, and they suggested that the predominant lesion was more likely to be in the testes rather than in the pituitary. In order to investigate this problem further, we have carried out a comprehensive study of pituitary function in a non-selected group of patients with idiopathic hemochromatosis. Materials and Methods Twelve male patients with idiopathic hemochromatosis were investigated. Their ages ranged Received December 22, 1975.
866
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 18 December 2014. at 06:45 For personal use only. No other uses without permission. . All rights reserved.
867
PITUITARY IN HEMOCHROMATOSIS (Actrapid) in doses varying from 0.2 U-0.5 U/kg BW. Blood samples were taken in the basal state for measurement of testosterone, sex hormone binding globulin capacity (SHBGC), luteinizing hormone (LH), follicle stimulating hormone (FSH), thyrotrophic hormone (TSH), human growth hormone (GH) and cortisol. Further samples were withdrawn at thirty and sixty min for all of these measurements with the exception of testosterone and SHBGC. In addition samples were withdrawn at ninety min for HGH and cortisol. On a subsequent occasion basal samples were taken for measurement of serum prolactin in ten patients. Serum LH and FSH were measured by specific double antibody radioimmunoassay (9). Results were expressed as U/L of M.R.C. Human Pituitary Standard (69/104). GH was measured by double antibody radioimmunoassay (W.H.O. First I.R.P.). Likewise serum TSH was measured by double antibody radioimmunoassay and the results expressed in mU/L of M.R.C. Human Pituitary Standard (68/38). Serum testosterone was measured by radioimmunoassay (10) using antibodies raised as described by Erlanger et al. (11). Serum extracts were purified by two stage thin layer chromatography prior to assay. SHBGC was measured by the method of Rudd et al. (12). Serum prolactin was measured as described by Glass et al. (13), but using NIH V-L-S 2 for iodination. Serum cortisol was measured by the technique of competitive protein binding (14).
Results In nine of the twelve patients features suggestive of hypogonadism were observed. In two of these cases the features were marked, in five cases only mild features were noted, while in the other two cases the only features possibly attributable to hypogonadism were subjective (reduced libido and impotence); (Table 2). The most common objective feature suggestive of hypogonadism was reduced body hair. This was seen in five patients and was charTABLE 2.
TABLE 1. Details of 12 patients with hemochromatosis (10 diabetics) Years
Known duration of hemochromatosis Known duration of diabetes
15
6
3
2
1
2
3
2
3
acterized by an absence of chest hair, reduced axillary hair, and female distribution of pubic hair. In all cases it was of gradual onset and not attributable to racial or genetic factors. Gynecomastia was of slight degree in both patients in whom it occurred. Neither patient was taking any drugs known to stimulate breast tissue. Assessment of the subjective features of hypogonadism (loss of libido and impotence) is a particularly difficult problem, especially in patients in the older age group. However, when compared to a control group of healthy subjects, libido was deemed to be reduced in seven instances. Impotence was total in the four patients in whom it occurred. Figure 1 shows the basal testosterone values for ten patients in whom the measurements were made. In two cases the values were below the normal range. In both instances sex hormone binding capacity was normal. Sex hormone binding capacity was also normal in all of the other cases. Likewise, serum prolactin levels were within the normal range in all patients in whom the measurements were made. Figure 2 shows the mean results for LH and FSH. Also shown are the mean values in a control group of ten diabetics who were potent and who did not have hemochromatosis. The age range of the control group was 30 to 65 years (mean 41 years). The mean values for the patients with hemochromatosis are within the normal
Details of clinical features of hypogonadism
Libido
Impotent
Testicular atrophy
Body hair
Gynecomastia
7
4
3
5
2
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 18 December 2014. at 06:45 For personal use only. No other uses without permission. . All rights reserved.
868
JCE & M • 1976 V'ol 43 • No 4
WALSH ETAL.
60 .
50 .
values did not increase in two of these four patients, while in all four cases serum cortisol levels rose only marginally, or not at all. In all cases, however, the basal cortisol values were within the normal range. Discussion
§
40 J
O
30 .
o E c
Q£
UJ HO hto
20 .
10 .
10 PATIENTS WITH HAEMOCHROMATOSIS FIG. 1. Basal testosterone levels in 10 patients.
range, and do not differ significantly from the values for the control group (P > .05). On an individual basis, however, both the LH and FSH responses to LHRH were abnormally low in two patients with hemochromatosis. Both of these patients had low serum testosterone levels. The overall response to TRH was normal (Table 3). However in one patient TSH failed to rise. This patient had also failed to respond to LHRH. The growth hormone and cortisol responses to IV insulin are shown in Figs. 3 and 4. It should be noted that hypoglycemia (blood sugar
