Testosterone treatment of men with idiopathic hemochromatosis.

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 +/- 7.4 ng/ml) and estradiol (from 17.4 +/- 6.3 to 38.5 +/- 14.2 pg/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 4-weekly 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.

Adrenal incidentaloma and patients with homozygous or heterozygous congenital adrenal hyperplasia.

Adrenal tumors are being detected more frequently in consequence of the wider application of increasingly sensitive radiological investigation techniques. According to the working hypothesis that more silent adenomas could develop from hyperplastic tissue areas under increased stimulation of the adrenal cortex, heterozygous and homozygous patients with congenital adrenal hyperplasia (CAH) were studied. A high incidence of adrenal masses, nearly 82% in homozygous and 45% in heterozygous patients, was found. There was no correlation between tumor size and serum 17-hydroxyprogesterone concentrations. These tumors are, therefore, probably silent adenomas. On the basis of these results, CAH should always be ruled out in the case of incidentally detected adrenal masses. Since CAH is a relatively frequent disease, and the adrenal carcinoma belongs to the rarest malignant tumors, a malignant transformation of these tumors seems to be unlikely.

Age-related changes in 11 beta-hydroxyandrostenedione concentration in normal and osteoporotic women.

The secretion of dehydroepiandrosterone (DHEA) and its sulfate is known to decline gradually with advancing age. Furthermore DHEA is known to be significantly lower in osteoporotic subjects than in normals. Recently 11 beta-hydroxyandrostenedione (11-OHA) has been proposed as an important indicator of the adrenal source of hormone excess in different hyperandrogenic states. In the present study we measured 11-OHA in 224 normal women aged 20-79 yr and 130 osteoporotic women aged 40-79 yr. RIA of 11-OHA was performed with highly specific antiserum raised in rabbits. The mean 11-OHA serum concentration was 2.20 +/- 0.90 ng/ml in normal women and 1.75 +/- 0.58 ng/ml in osteoporotic women. In contrast to DHEA there was no age-related decrease in 11-OHA serum concentrations in normal and osteoporotic women. Osteoporotic subjects showed statistically significantly lower 11-OHA serum concentrations than normal women. Therefore low serum 11-OHA might represent a further risk factor for osteoporosis.

[Adrenogenital syndrome--today a radiologic diagnosis?]. / Adrenogenitales Syndrom--heute eine radiologische Diagnose?

The following case report shows the course of disease of a 37 year old man, who showed the classical symptoms of an untreated congenital adrenal hyperplasia. But only when an adrenal tumor accidentally was detected, the endocrinological tests and the diagnosis of the congenital adrenal hyperplasia were made. By this diagnosis the planned adrenalectomy could be avoided now.

Cushing's syndrome due to ACTH-production of an ovarian carcinoid.

The case of a 56-year old woman with severe Cushing's syndrome due to ovarian ACTH-production is described. Both clinical picture and biochemical pattern were consistent with the ectopic ACTH syndrome. ACTH was found by specific immunohistochemical staining in a carcinoid tumor of the patient's right ovary. In contrast, pituitary cells exhibited immunoreactive ACTH to only a minimum extent.

Abnormalities in estrogen, androgen, and insulin metabolism in idiopathic hemochromatosis.

Of 44 male patients with idiopathic hemochromatosis who were diagnosed at an early stage without morphological or biochemical evidence of liver disease, 25% suffered from impotence and 34% manifested glucose intolerance. Impotence was correlated with a 50% reduction in plasma testosterone, resulting from a 63% decrease in testosterone production. Testicular atrophy was caused by insufficient secretion of gonadotropins due to the selective accumulation of iron in gonadotropic cells of the pituitary gland. However, peripheral sexual hormone metabolism, in particular the conversion of androgens to estrogens, remained unaltered. It was therefore possible to employ substitution therapy successfully with testosterone in these men, and hyperestrogenism was not observed as a side effect. The pathogenetic factors in the development of diabetes mellitus in patients with idiopathic hemochromatosis include impaired insulin secretion caused by the selective deposition of iron in B-cells of the pancreas and insulin resistance due to iron accumulation in the liver. In particular, the insulin resistance is markedly improved after depletion of body iron stores by phlebotomy treatment, resulting in lower insulin requirements in patients with insulin-dependent diabetes as well as improvement of carbohydrate metabolisms in about half of the patients with non-insulin-dependent diabetes. We have concluded that hypogonadism and carbohydrate intolerance are caused by the specific distribution pattern of excess iron in the organism, accompanied by functional impairment of affected parenchymal cells.

[Silent adrenal gland tumors in patients with adrenogenital syndrome]. / Stumme Nebennierentumoren bei Patienten mit Adrenogenital Syndrom.

Adrenal tumors accidently detected by CT scan are increasingly seen in patients without clinical signs of adrenal diseases. We studied whether enhanced adrenal stimulation is of importance in the development of adrenal tumors. For this purpose 22 patients with adrenogenital syndrome (AGS) were studied by CT scan. One of these patients suffered from C-11 beta-hydroxylase-, one from C-3 beta-hydroxy steroid dehydrogenase-, and 20 from C-21-hydroxylase deficiency. The average adrenal size of these patients was 506 +/- 79 mm2 as compared to 132 +/- 8 mm2 in the controls (P less than 0.001). Only two patients with the late onset form revealed adrenal glands of normal size. There was a significant correlation between adrenal size and patients' age (P less than 0.01). Females with the simple virilizing form revealed adrenal glands larger than those of the late onset form (640 +/- 169 vs 308 +/- 56 mm2). Eighteen patients with AGS exhibited one (n = 11) or several (n = 7) adrenal tumors, the size of which was 5-9 mm in diameter in 9, 10-20 mm in 7, and more than 50 mm in 2 patients. There was a significant correlation between adrenal hyperplasia and tumor diameter (P less than 0.001). No correlation was found between tumor size and plasma concentrations of testosterone or 17-hydroxyprogesterone, patients' age at the time of diagnosis, or clinical signs of androgenization. Again, tumors were larger in females suffering from the simple virilizing form of AGS than in those with the late onset form (14.8 +/- 5.5 vs 7.7 +/- 0.8 mm).(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical and endocrinological characterization of two subjects with Reifenstein syndrome associated with qualitative abnormalities of the androgen receptor.

The androgen receptor in fibroblasts cultured from a biopsy of scrotal skin from 1 subject with Reifenstein syndrome has been found to be normal in amount and to bind dihydrotestosterone with normal affinity but to be qualitatively abnormal as evident by thermolability and instability upon ultracentrifugation. The family study of this subject and endocrine studies document androgen resistance in the index patient and his affected uncle. These findings provide evidence for X-linkage of this disorder, and suggest that the mutations that give rise to this phenotype are probably allelic to the mutations of the androgen receptor that cause testicular feminization.

Aminoglutethimide without hydrocortisone in the treatment of postmenopausal patients with advanced breast cancer.

In a phase II study, 38 evaluable patients with advanced progressive breast cancer were treated with 4 X 250 mg of aminoglutethimide per day without hydrocortisone supplementation. Partial remissions were observed in five patients (13%), with a median duration of 9 months (range, 7-15), and stable disease was observed in 17 patients (45%), with a median duration of 4 months (range, 2-11). The recorded side effects (CNS, cutaneous, gastrointestinal) were tolerable and transient and required drug discontinuation in only four patients. Serial determinations of serum hormone levels during aminoglutethimide treatment revealed a significant decrease in estradiol and an increase in gonadotropins, testosterone, and progesterone. No patients had adrenal insufficiency. In contrast, despite prolonged aminoglutethimide treatment and persisting hypoestrogenemia, both cortisol levels and adrenal responses to ACTH remained unaltered. It is concluded that aminoglutethimide alone is effective in the treatment of postmenopausal patients with breast cancer. Moreover, based on the present findings, a prospective randomized study is warranted to show that hydrocortisone supplementation appears to not be mandatory, either for increase in efficacy or for decrease in side effects of the treatment.

The measurement of 11 beta, 17 beta-dihydroxy-4-androsten-3-one (11 beta-hydroxytestosterone) by radioimmunoassay in human plasma.

A radioimmunoassay (RIA) is described for the measurement of 11 beta,17 beta-dihydroxy-4-androsten-3-one (11 beta-hydroxytestosterone) in human plasma. The reliability criteria of the new RIA were similar to those of other steroid hormone radioimmunoassays. The mean plasma 11 beta,17 beta-dihydroxy-4-androsten-3-one level for healthy young subjects was 1.31 +/- 0.32 nmol/l (means +/- SD) in males and 1.19 +/- 0.35 nmol/l in females at 8 a.m.; during the night, there was a marked decrease, and at 11 p.m. the recorded values were 0.41 +/- 0.15 nmol/l and 0.46 +/- 0.14 nmol/l, respectively. During the corticotropin stimulation test, 11 beta,17 beta-dihydroxy-4-androsten-3-one increased from 1.03 +/- 0.33 nmol/l to 1.31 +/- 0.41 nmol/l, while in dexamethasone suppression tests a decrease from 2.04 +/- 0.82 nmol/l to 0.25 +/- 0.05 nmol/l was seen. In contrast, chorionic gonadotropin administration on 3 consecutive days did not influence plasma concentrations of 11 beta,17 beta-dihydroxy-4-androsten-3-one.

Biochemical and histochemical studies on the pituitary-testicular axis in obese (C57Bl/6J-ob/ob) mice.

Male C57Bl/6J-ob/ob mice (4 months old) and their homozygous lean controls were compared with respect to pituitary LH secretion and functional parameters of purified Leydig cells in vitro. Compared with controls, obese mice showed reductions in the following parameters: Plasma testosterone levels (reduced by 57%), hCG-stimulated testosterone formation in vitro (by 31%), conversion of progesterone to androgens by Leydig cells (by 39%), and GnRH-stimulated LH secretion (by 26%). Lipid accumulation and a 37% decrease in naphthylesterase activity in the Leydig cells as well as hyperplasia of pituitary gonadotrophs were observed histochemically in obese mice. The changes in testicular endocrine function in obese mice are interpreted as consequences of pituitary dysfunction.

Circadian and seasonal variations of glucocorticoid receptors in normal human lymphocytes.

Circulating human lymphocytes are known to contain specific glucocorticoid receptors. Using a competitive binding whole cell assay, we have examined the binding of [3H] dexamethasone to peripheral lymphocytes of normal male subjects. Lymphocytes were found to contain 2000-10000 glucocorticoid receptor sites/cell and the Kd value was in the range of 0.5-9 X 10(-9) M. The number and affinity of glucocorticoid receptors did not change throughout a 1-year observation time. In contrast, there was a significant diurnal variation in receptor content (38% higher at 11 p.m. than at 8 a.m.), while receptor affinity did not change.

[Stability of steroids in plasma over a 10-year period]. / Stabilität von Steroiden im Plasma über einen Zeitraum von 10 Jahren.

In order to examine whether plasma samples may be used for steroid analysis after long periods of storage, cortisol, testosterone, oestrone and oestradiol were remeasured in samples, which had been analysed 1.3-10.8 years earlier. The method for the measurement of these steroids was unchanged over this period. The results demonstrate that at a temperature of -25 degrees C steroids remained stable. Only cortisol and testosterone concentrations showed a small, insignificant decrease (6-9%) after 3 to 4 years of storage. These differences are well within the range of the precision of the method (interassay variation), which over a period of 11 years was 9.4%, 8.0%, 10.0% and 9.5% for cortisol, testosterone, oestrone and oestradiol, respectively. It is concluded that steroid hormones in human plasma are stable in our laboratory, and that they might be analysed even after more than 10 years of storage at -25 degrees C.

In-vitro studies of the development of pituitary and testicular functions in diabetes (C57Bl/KsJ-db/db) mutant mice.

The hypothesis that male diabetes mutant mice (C57Bl/KsJ-db/db) are suffering from impairment of testicular steroidogenic function and pituitary LH release was tested. A smaller postpubertal increase of testicular weight and a reduction of plasma testosterone and androstenedione levels by 65% at 17 weeks of age were most obvious from the comparison to homozygous lean controls. The ability of constant amounts of Leydig cells, either in crude interstitial cell or in purified Leydig cell suspensions, to respond to maximal doses of hCG or cyclic AMP-was reduced by at least 40% in adult diabetes mice. This defect could be attributed to a 40% decrease of steroid-17 alpha-monooxygenase activity as compared to lean mice. No differences occurred, however, if Leydig cells were submaximally stimulated. GnRH-stimulated pituitary LH release was not significantly changed. The impairment of testicular steroidogenic function in diabetes mutant mice may represent a further aspect of infertility of these animals and of diabetes mellitus.

[Alcohol and fertility: sex hormones]. / Alkohol und Fertilität: Sexualhormone.

Alcohol is a noxious substance with considerable effects on men's potency and fertility. In case of acute intoxication as well as in case of long-term effects of ethanol there is a significant decrease of testosterone and a consecutive increase of gonadotrophin LH resulting in primary hypogonadism. Moreover, chronic alcoholism leads to organic damages of the testes and the liver. Consequently the clinical symptoms and laboratory data show complex changes. Aside from the decrease of testosterone there is an increase of oestrogens (chiefly of estrone); thus increased oestrogenial effects are found in connection with changes regarding synthesis, metabolism, conversion, as well as intravascular and intracellular (receptors) binding proteins. These patients often show gynaecomastia.

Conversion of androgens to estrogens in idiopathic hemochromatosis: comparison with alcoholic liver cirrhosis.

Hypogonadism is common in patients with some liver diseases, such as idiopathic hemochromatosis (IHC) and alcoholic cirrhosis (AC). However, gynecomastia, a typical feature in AC, does not occur in IHC. To determine the hormonal basis for this difference, the following parameters were determined in patients with IHC and AC as well as in normal men: plasma concentrations of androgens and estrogens, metabolic clearance and production rates of androstenedione and testosterone, and the contribution of peripheral conversion of androstenedione and testosterone to the circulating estrogens. Severe impotence in both patients with IHC and those with AC was associated with more than 50% reduction in plasma testosterone. The reduction was due to 63% and 70% decreases in testosterone production in IHC and AC, respectively. The MCRs were less affected in IHC and AC (19% and 37% reductions, respectively). In IHC, the fall in testosterone concentrations was accompanied by decreased production and plasma concentrations of androstenedione, a precursor for estrogen synthesis. In contrast, production and plasma concentrations of androstenedione were significantly increased in AC. Patients with IHC had estradiol und estrone levels similar to those in normal men (mean +/- SD, 16.2 +/- 4.6 vs. 20.3 +/- 3.7 pg/ml; P = NS), whereas in AC, estradiol and estrone were significantly elevated (38.0 +/- 5.3 and 68.5 +/- 17.2 pg/ml, respectively). In IHC, sex hormone-binding globulin levels were in the same range as in the normal men, whereas sex hormone-binding globulin was increased in AC. In IHC, the instantaneous contribution of plasma androstenedione to estrone and estradiol was normal, whereas that of plasma testosterone to plasma estrogens was decreased by about 50%. In contrast, in AC, the instantaneous contribution of plasma androstenedione to estrogens was greatly enhanced, and that of testosterone was in the normal range. Since the MCRs of androgens and the conversion ratios of androgens to estrogens indicate normal peripheral metabolism of sex hormones in IHC, decreased androgen formation implies decreased testicular synthesis. This was confirmed by a significantly decreased LH level in IHC (5.5 +/- 1.9 vs. 10.5 +/- 3.1 mU/ml in normal men), indicating pituitary failure. In AC, however, increased LH (20.0 +/- 2.7 mU/ml) may be indicative of primary testicular failure. These results confirm clinical features of hypogonadism and normal estrogenic activity in patients with IHC.(ABSTRACT TRUNCATED AT 250 WORDS)

Androgen and estrogen response to adrenal and gonadal stimulation in idiopathic hemochromatosis: evidence for decreased estrogen formation.

Gonadal function in idiopathic hemochromatosis (IHC) was evaluated by comparing clinical features and levels of sex hormones in 10 male patients with IHC (cirrhosis, 4; fibrosis, 6), 6 male patients with alcoholic cirrhosis (AC) and 10 healthy, age-matched controls. Impotence was present in 9 IHC and all AC patients and was associated with decreased plasma testosterone levels. However, gynecomastia, a feature in all patients with AC, was not present in IHC, and plasma sex hormone binding globulin was normal. Patients with IHC showed significantly lower basal estradiol levels (17.7 +/- 6.3 pg per ml) than did controls (28.5 +/- 8.5 pg per ml), and low LH levels (p less than 0.01), which were insufficiently stimulated by luteinizing hormone releasing hormone (n = 8) as well as a decrease in prolactin concentration (2.9 +/- 1.4 vs. 5.9 +/- 1.9 ng per ml in the controls) suggesting pituitary failure. Synthesizing capacity of sex hormones was determined by adrenocorticotropic hormone and human chorionic gonadotropin administration. Basal and stimulated levels of androstenedione and cortisol indicated normal function of the adrenals in IHC. However after adrenocorticotropic hormone, estrone levels increased to only 16.2 +/- 8.4 pg per ml (controls, 27.3 +/- 4.7 pg per ml; p less than 0.01). Increments of estrone (12.5 +/- 9.2 pg per ml) and estradiol (17.9 +/- 11.6 pg per ml) were also lower in IHC following human chorionic gonadotropin administration than in controls (26.0 +/- 7.2 and 37.5 +/- 11.4 pg per ml, respectively). In contrast, plasma human chorionic gonadotropin raised testosterone levels 3.3-fold in IHC and 2.2-fold in controls.(ABSTRACT TRUNCATED AT 250 WORDS)