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Hereditary deficiency of the thyroxine-binding globulin (TBG) has been described in 17 families, in 12 of which it is X-chromosomal inherited. Different modes of transmission can be assumed for some of the other families but are not yet warranted. Genetic elevation of TBG has been described in 7 families. This trait is presumably uniformly X-chromosomal inherited.

Plasma concentrations of thyroid stimulating hormone (TSH) were measured radioimmunologically in primary hypothyroid patients after administration of organic iodine (Endojodin®), iodoaminoacids, synthetic corticotrophin (ACTH) and cortisone. During intravenous injections of Endojodin® for 5 days there was a slight but significant decrease of plasma TSH. After oral application of 6 different l-iodoaminoacids in high doses over several days we observed in rough relation to their biologic activity a fall in TSH levels in plasma. D-thyroxine, however, was also active under these conditions. During infusions of synthetic ACTH (β1-24, β1-39) and cortisone in two different doses the TSH levels in primary hypothyroid patients decreased in the same way. Synthetic thyrotrophin releasing factor (TRF) after intravenous application was followed by an abrupt rise in plasma TSH concentration in euthyroid and primary hypothyroid persons. In secondary hypothyroid and hyperthyroid patients no or only slight effects were observed in the TSH levels. The possible employment of TRF in the diagnosis of thyroidal or hypophyseal disorders is discussed.

In a female patient, aged 24, neither gonads nor internal genitalia could be found, only a penis-like formation of 3–4 cm in her pubic region. A peripheral blood culture revealed 46 chromosomes with a normal X but deleted Y. Although no rudimentary gonads could be found at laparotomy, one can conclude by comparison with other forms of intersexuality that the defective Y must have induced an incomplete testisanlage. This primitive testis was able to suppress formation of female genitalia but unable to complete masculinisation. As a result an intersexual state developed with rudimentary Wolffchen and Müllerian ducts.

Pimozide, a specific blocker of dopamine receptors, was administered orally to 10 diabetics for 2 days before an arginine-hydrochloride infusion. In 8 healthy volunteers and 20 diabetics exercise tests on a bicycle ergometer were performed with a load of 100 Watts and 50 Watts respectively without or after a single dose of pimozide 30 min before the test. In 4 male diabetics day profiles of growth hormone (GH) were estimated without and during treatment with pimozide for 4 days. The arginine and exercise induced GH release was found to be significantly lowered by pimozide, whereas the marked spontaneous fluctuations in the diabetics were even enhanced by pimozide. These data support the concept of the involvement of dopaminergic stimulation in the response of GH to arginine and exercise. The spontaneous fluctuations of GH, however, seem to be regulated by other neuroendocrine mechanisms.

The cold agglutinin disease is a hemolytic anemia induced by antibodies. Beside other etiological factors the disease is associated with tumors.

A radioimmunoassay capable of detecting 300 fg somatostatin has been developed and levels of the polypeptide in gastrointestinal tissues from man, dog, and rat have been measured. Rapid freezing of collected samples and careful control of extraction is necessary. Concentrations in different regions of dog antrum (425 +/- 50 to 773 +/- 254 ng/g tissue) are similar to those in antrum from duodenal ulcer patients and control subjects: 614 +/- 125 and 465 +/- 104 ng/g tissue respectively. Levels in histologically normal human pancreas (253 +/- 43 ng/g tissue) are comparable with those in dog pancreas (333 +/- 66 ng/g tissue), whereas in two cases of neonatal hypoglycaemia the concentration exceeded 3000 ng/g tissue. On gel chromatography the majority of immunoreactive somatostatin elutes as the synthetic tetradecapeptide and a small fraction as a larger species.

The hypothesis that goitrogenesis in iodine deficiency can be attributed to the stimulatory effect of thyrotropin (TSH) on the thyroid gland and has long been held to be valid. The task of this review is to describe the reasons why this concept is being challenged. In addition, we report on the autoregulation of the thyroid gland and on in vitro investigations dealing with TSH as a growth factor, which have yielded conflicting results. Finally, we summarize preliminary studies comparing the therapeutic effect of thyroxine and iodine on goiter size. In comparison to thyroxine, iodine application in doses of 300-500 micrograms/day may represent an equally effective way of treatment in areas of endemic goiter, especially in younger patients. In this age group, the risk of side-effects, e.g., iodine-induced thyrotoxicosis, should be low.

SUMMARY In nine patients with thyrotoxicosis (three patients with ophthalmopathy, one patient with T3 thyrotoxicosis) we followed plasma levels of triiodothyronine (T3) and thyrotoxine (T4) and the TRH induced TSH release before and under treatment with propythiouracil (PTU), carbimazole or methimazol. The patients were observed for 2-8 months and did not receive any thyroid hormones during this time. Before treatment the TSH responses to TRH were absent in all patients. After commencement of antithyroid drug therapy the T3 and T4 plasma values decreased to normal (T3) or subnormal levels (T4) within 1-5 weeks and the patients became euthyroid, but at that time the TRH test was still negative in all patients. Moreover, there was a lag of between 2 weeks and 4 months in five of the patient before the TRH test became positive. The duration of this lag could not be correlated with any data of the history or the clinical signs. Several possible explanations for this observation are discussed. Our results suggest that the TRH-test is not suited for the control of the therapeutic effect of antithyroid drug therapy.

According to Bayes' rule the predictive value (PV) of a diagnostic test (= probability of disease if the test is positive) depends on the prevalence of the disease (= a priori probability), the sensitivity (c1) and the specificity (c2) of the test. A new variable has been introduced, the predictive factor (c), which is calculated as follows: c = c1/(c1 +1 -c2). Since the PV only depends on this factor and on the prevalence, the calculation is much easier and a general graphical solution is possible. This simplification renders several additional advantages and facilitates the understanding of the dependence of PV on prevalence.

Two years ago a work group of the GMDS was founded which is devoted to methods of prognosis estimation and decision making (“Methoden der Prognose und Entscheidungsfindung”). This group is trying to compile a catalogue on the requirements for checking diagnostic tests. Together with other clinicians we are participating in this group. Our main goal is that the catalogue should not become so complicated and sophisticated that clinicians will never read or use it. The problems we are faced with in looking at various diagnostic tests are much more basic and much simpler than the problems discussed in the work group.

Eight diabetics were found among 464 children, mean age 11.2 years, of 311 unselected insulin-treated mothers. By a method of age correction the total diabetes prevalence among the children at the age of 25 years was calculated as 3.4%. Three children were non-insulin dependent and these patients and their mothers may belong to the autosomal dominant type of diabetes, so-called MODY. In two of the other five families the fathers also had insulin-dependent diabetes; in two more cases first or second degree paternal relatives were insulin-dependent diabetics. Thus the prevalence of insulin-dependent diabetes among the children of insulin dependent mothers married to non-diabetics is calculated as 1.5% at the age of 25 years.

We offered a questionnaire to 52 physicians in order to study the appreciation of the fecal occult blood test as an example of a diagnostic procedure. We asked for an indication of the overall appreciation of the test, and for an estimation of the probabilities of colorectal cancer before the test and with a positive or a negative test result--each of them for three situations with different a priori probabilities. The answers demonstrated that the estimated value of the test, representing the personal experience of the physicians is very low (predictive factor between 0.61 and 0.78). About half of the physicians' estimations showed no improvement of probability by using Haemoccult. This contrasts with the expressed very positive general opinion about Haemoccult testing, including its use in symptomatic patients. This result underlines the necessity of careful evaluation of diagnostic tests.

A female patient with the following symptoms has been observed: complete absence of subcutaneous fat on the arms and legs, well developed adipose tissue on the trunk and face, severe hyperlipidemia, eruptive xanthomas, insulin resistant diabetes mellitus with lack of ketoacidosis, hepatomegaly and elevated basal metabolic rate. The patient thus exhibited all characteristics of lipatrophic diabetes (Lawrence type of diabetes). The mother and a sister of the patient were found to have the same peculiar appearance and a slight hyperlipidemia but no diabetes mellitus. The combination of this type of partial lipodystrophy with severe hyperlipidemia, insulin resistant diabetes mellitus without ketoacidosis and elevated basal metabolic rate was further observed in 2 unrelated patients without known familial occurrence. Thus partial lipodystrophy of the extremities is another, previously undescribed, syndrome associated with the Lawrence type of diabetes mellitus. In the 1 family the syndrome of lipodystrophy and hyperlipidemia is dominantly inherited. Besides the autosomal recessively inherited syndrome of congenital generalized lipodystrophy there is a heterogenous group of dominantly inherited syndromes with various types of lipodystrophy.

HLA-typing was performed in two groups of juvenile-onset diabetics, one with (n = 58) and one without (n = 109) a family history of the disease. The association of this type of diabetes with certain HLA antigens (excess of B8 and B15, shortage of B7) was confirmed. No heterogeneities could be established between the two groups. This suggests that the aetiologic basis in single and familial cases of juvenile diabetes is the same. The hypothesis, that the B8 associated gene is more penetrant than the B15 associated gene, cannot be confirmed. Haplotypes were determined in families with one and two diabetic siblings. The findings of high haplotype concordance among diabetic siblings was confirmed: concordance of 2, 1 and 0 haplotypes in 7, 5 and 3 pairs respectively. There was a low degree of haplotype concordance between diabetics and nonaffected siblings in the families with two diabetics: 2, 1, and 0 haplotypes in 2, 8 and 6 pairs respectively. This led to the hypothesis of negative selection against these HLA-linked "diabetogenic" genes. This tendency was not, however, observed in families with only one diabetic. The report of a high recombination rate in families with juvenile diabetics could not be confirmed.

Somatostatin inhibited gastric acid secretion significantly in three ZE patients, while serum gastrin was lowered only in two. A direct inhibition of pentagastrin-stimulated acid secretion by somatostatin was demonstrated in three healthy volunteers and four patients with duodenal ulcer disease. Somatostatin reduced betazole-stimulated gastric acid secretion to a lesser degree. The immunohistological demonstration of somatostatin-producing cells apposite to antral G-cells suggest a physiological role of somatostatin in the regulation of gastrin secretion in man.

The fundamental terms in the evaluation of diagnostic tests are described and the differences to corresponding test parameters in clinical chemistry are emphasized. The derivation of a two-by two contingency table is explained in detail and basic characteristics of diagnostic tests, i.e. sensitivity and specificity as well as their independence of the prevalence (in the sense of a-priori-probability) is pointed out. The importance of the so-called predictive values is shown graphically, also the problem of selecting a cut-off-level (discrimination value) for the evaluation of quantitative data. The various attempts to find a single value for the description of a diagnostic test are discussed and it is stressed that there is no principal necessity to use other terms than those mentioned above. Nevertheless it is possible to give a prevalence-independent measure which has some additional advantages in rating and comparing simple diagnostic tests.

In 14 patients being treated with fluoride preparations for osteoporosis histomorphometric analysis of iliac biopsies showed that the volume of the mineralised spongiosa had increased by more than 20% above initial level in eight instances. The volume of the osteoid in ten cases had also increased, generally most markedly in the first year. In some cases the clinical symptoms corresponded to the histomorphometric findings. The results suggest that fluoride treatment of osteoporosis can be continued beyond one year. But this should only be done under precise control also of histological bone studies because in three of the patients the spongiosa volume had reached high normal values already after one to three years of treatment.

Determination of the basal and LH-RH-stimulated luteinizing hormone (LH) levels as well as testicular morphology in patients with surgically treated (n equals 112) and non-treated (n equal 96) undescended testes gave the following results: Unilateral of bilateral undescended testes are probably a form of primary, secondary or tertiary hypogonadism. In a high percentage abnormal basal and stimulated serum-LH values can be demonstrated. The testosterone values are within normal limits. The gonadal tissue damage in the abnormally situated testes of prepubertal boys seem to be congenital. With increasing duration of the malposition, particularly after the onset of puberty, a secondary tissue degeneration in the dystopic testis occurs. The damaging influence on the testicular tissue caused by the abnormal position seems to take place mostly at the end of prepuberty. A decrease in the number of spermatogonia in the tubuli of dystopic testes during the first 2 years of life is physiological. A surgical repositioning of the dystopic testis into the scrotum within the first 2 years of life is not indicated. Damage of gonadal tissue in the scrotal testis caused by the dystopic testis in unilateral maldescent could not be demonstrated. The optimal space for orchidopexy is between the third and fifth year of life.

One of the main purposes in studying the genetics of diabetes mellitus is to determine heterogeneities. Many special types of diabetes, with various types of etiology and pathogenesis and sometimes distinct clinical pictures, have been described. After separation of these special types all remaining diabetics are summarized as idiopathic diabetics. There is conclusive evidence that heredity plays a major role in the eiology in this group of idiopathic diabetics. It is very unlikely that it represents a homogeneous disease. Most probably it consists of various types of diseases with different etiologies, both exogenous and genetic, and even the genetic diabetes is most probably heterogenous. As long as we are not able to subdivide the idiopathic diabetes according to etiology, pathogenesis, or clinical type, we have to confine ourselves to genetic differences between groups of patients which may be classified according to sex, age at onset, weight, or other measurable parameters.

Screening for early stages is considered to be the most favorite method to improve the prognosis of cancer. As for colorectal carcinoma it is the search for invisible amounts of blood in the stool which seems to appear as an early symptom in the development of a malignant colon tumor. There are a lot of enthusiastic reports about this screening method, called “fecal occult blood testing”. Especially the widespread recommendation of the Haemoccult-test and the conviction that its effectiveness has been proved are aspects of general agreement. The subject of this paper is to compare the established original data about Haemoccult screening with this general appreciation, as it is found in the secondary literature.

In the therapy of metastatic breast cancer MAP was used with different dosages and different forms of administration. Pharmacokinetics and pharmacodynamics were investigated. MAP plasma concentrations are dose dependent with great interindividual variation. The cortisol suppressive effect is dependent on plasma concentrations with only narrow interindividual variability. The oral administration of the crystal suspension is equivalent to the administration of tablets concerning plasma levels und endocrine effects. The therapy schedule for i.m. application used here leads to lower MAP plasma concentrations and correspondingly to a minor endocrine effect than in oral therapy. Tumor effective and cortisol suppressive plasma concentrations seem to have the same level.

One of the major steps forward in the field was the perception that diabetes mellitus is not an etiologically or pathogenetically uniform disease. All investigations into the genetics of diabetes had been in vain as long as this heterogeneity was not considered.

One of the central effects of MAP is the intrinsic glucocorticoid activity. In the therapy of metastatic breast cancer with high dose MAP the cortisol like effect could be shown even in long term treatment. The cortisol like activity of MAP leads via the suppression of ACTH to a decrease of endogenous cortisol secretion. This cortisol like activity of MAP is sufficient to replace the obligate cortisol substitution in the therapy of metastatic breast cancer with aminoglutethimide. Thus within the therapy of metastatic breast cancer the combination of two endocrine acting drugs is possible.

Iodine-induced thyrotoxicosis due to iodine application in high amounts in patients with circumscript or disseminated thyroid autonomy, is complicated by a prolonged course, mainly due to a resistance to conservative therapy with thiourea derivates. We therefore decided to perform an early subtotal thyroidectomy in 24 thyrotoxic patients. This measure is in contrast to the common opinion that surgery should only be performed after normalization of thyroid hormones. In all 24 patients with severe hyperthyroidism, including three patients with thyroid storm, hormone levels decreased within a few days after surgery to normal or subnormal values and the clinical picture of thyrotoxicosis disappeared. In the case of thyroid storm the signs of disorientation normalized within 1-3 days. One patient died five weeks after surgery due to severe concomitant diseases. One patient exhibited transitory respiration distress and another had postoperative hypocalcemia. In 13 patients L-thyroxine replacement became necessary due to subclinical or clinical hypothyroidism. Surgery as a early treatment for thyrotoxicosis should be reserved for patients with severe illness where conservative treatment has been shown to be ineffective. In rare selected cases, when a rapid normalization is required, surgery without preoperative treatment seems to be justified. The effect of surgery was impressive in all our cases and there were only minor perioperative complications.

Die Erkenntnis, das der Diabetes mellitus nicht ein atiologisch, pathogenetisch oder klinisch einheitliches Krankheitsbild darstellt, gehort zu den wichtigsten Fortschritten der klinischen Diabetologie. Alle Untersuchungen zur Genetik des Diabetes waren von vornherein zum Scheitern verurteilt, soweit sie diese Heterogenie nicht berucksichtigten. In den letzten Jahrzehnten wurden mehrere Versuche unternommen, ein geeignetes Klassifikationsschema des idiopathischen Diabetes zu entwickeln, das auch den genetischen Gegebenheiten Rechnung tragt. Obwohl weiterhin jede Klassifizierung mit gewissen Unklarheiten behaftet ist, sind in der WHO-Klassifikation von 1980 (Tabelle 1) die entscheidenden neuen Erkenntnisse der letzten Jahre in einem einfachen Schema zusammengefast, das sich bisher in Klinik und Forschung bewahrt hat [21].

Cold agglutinin disease is a normo- or macrocytic anemia due to antibodies, active under body temperature, mostly belonging to the immunoglobulin class M. Initially the agglutination of erythrocytes with acrocyanosis is reversible at body temperature. High antibody activity or long lasting period of coldness lead to intravascular or intrahepatic hemolysis, but high risk anemia is rare. Beside the idiopathic form, infection induced (especially infectious mononucleosis, cytomegalovirus, Mycoplasma pneumoniae, Klebsiella), and drug induced (especially quinidine, alpha methyldopa, penicillin, para-aminosalicylic acid, various analgetics, sulfonylurea), tumor associated (especially malignant lymphomas), and autoimmune disease associated (especially systemic lupus erythematosus) cold agglutinin anemias are discribed. "Cross reacting antigenity" to the hemolysing agent and the membrane of erythrocyte, exogenous induced changing of erythrocytic antigenity, and diversification concerning the production of antibodies are discussed as pathophysiological explanations.

From personal experience in 200 patients and after a careful review of the literature autonomous adenoma of the thyroid is discussed under three aspects: 1. Different ways of its pathogenesis are possible. None of them has been sufficiently proven. 2. Differentiation by scintigraphy into a compensated, partially decompensated stage does not correlate sufficiently with the concentration of thyroid hormones in the blood and the overall clinical picture. The TRH test is negative in about 90% of patients independent of the stage evaluated by scintigraphy. 3. The diagnosis of the disease by modern tools is critically reviewed.

Osteoporose ist die haufigste generalisierte Knochenerkrankung. Als einzige medikamentose Behandlungsform hat sich die Gabe von fluoridhaltigen Praparaten evtl. in Kombination mit Calcium oder Vitamin D durchsetzen konnen. Diese Behandlungsform ist jedoch mit einer Reihe von Unsicherheitsfaktoren belastet. So ist es bis heute unklar, welche F−-Spiegel im Serum unter der NaF-Therapie erreicht werden. Nahezu unbekannt ist die Bioverfugbarkeit der auf dem Markt befindlichen F−-Praparate. Wir wissen nicht, ob magen- oder dunndarmlosliche Praparate vorzuziehen sind. Die Dosierungsempfehlungen schwanken zwischen 20 und 120 mg NaF pro die, wobei zusatzlich noch umstritten ist, wie lange behandelt werden soll. Daraus resultiert die Frage nach der Kumulation von Fluorid in Korpergeweben. Umstritten ist ebenfalls, inwieweit die Kombinationsbehandlung von Vorteil ist. Die Problematik der Vertraglichkeit, der Nebenwirkungen und der Toxizitat wird widerspruchlich diskutiert. Daruberhinaus besteht Unklarheit zur Frage der Kontraindikationen.

Based upon preliminary observations that tumor response to MPA was correlated to cortisol suppression 42 patients were treated with MPA at different dose levels. 1500 mg MPA p.o. almost completely suppressed endogenous cortisol production in 23 out of 23 patients. Consequently, 51 patients with advanced stage metastatic breast cancer were treated with Medroxyprogesteroneacetate (HD-MAP) at a dosage of 1500 mg p.o. daily or 500 mg i.m. on 5 days per week. There were 5 complete and 7 partical remissions, 23 patients with no change and 10 with progressive disease. 7 patients were not evaluable. Clinical results correlated to plasma cortisol and prolactin blood levels bot not to LH, FSH, TSH, TBI, T3, T4, ACTH and aldosterone measurements. There was no patient with relapse and suppressed cortisol or normal prolactin measurements. The development of pituituary resistance to MPA is suggested. HD-MPA was equally effective in estrogen and/or progesterone receptor positive as in receptor negative patients. It is proposed that cortisol and prolactin determinations are useful to monitor for effective MPA treatment and the early detection of MPA resistance.

Seventy-seven patients aged more than 60 years from the iodine deficiency area of southern Lower Saxony with hyperthyroidism, diagnosed by assessment of thyroid parameters, showed a nonspecific disease picture with surprising frequency when compared with younger patients. Predominant characteristics were weight loss (86%), general weakness (78%), tachycardia (74%), reduced appetite (66%), exertional dyspnoea (60%), apathy, lack of initiative or depression (48%), and uncharacteristic abdominal complaints (20%). A goitre was not palpable in 30 patients (39%). Laboratory diagnosis was hampered by relative or absolute TBG deficiency and conversion inhibition in the form of a low-T3 syndrome as evidence of non-thyroidal changes in generalised disorders. Neither thyroxine nor triiodothyronine were increased in ten patients (13%). Only by additional routine estimation of the thyroxine-binding index (T3 in vitro test) as indicator of free binding capacity could the diagnosis be ascertained in these cases. The poor prognosis be ascertained in these cases. The poor prognosis of hyperthyroidism in the older age group necessitates generous use of specific diagnostic laboratory investigations in cases with suspicious symptoms.

Two kinds of medical treatment of endemic goitre (400 microgram of iodine, n=11, and 150 microgram of L-thyroxine, n=12) were compared in a double blind study with a placebo group (n=12) during a period of 12 months and an observation time of three months after cessation of therapy. The means of the neck circumference and of the estimated thyroid volume decreased significantly during treatment in both groups, whereas no significant difference was observed in the placebo group. The results in both therapy groups did not differ significantly from each other. No side effects or symptoms of hyperthyroidism were observed. During treatment the index of free thyroxine (FT4I) increased significantly in both the iodine and the thyroxine group and delta TSH after TRH decreased significantly. Total triiodothyronine (TT3) did not show significant alterations. Three months after cessation of therapy in the thyroxine treated group the mean FT4I dropped into the range before treatment, whereas it remained slightly elevated in the iodine group. In the thyroxine treated group the mean delta TSH was higher than its value before therapy. After withdrawal of iodine, however, the mean delta TSH remained decreased for three months. The study indicates that 400 micrograms of iodine per day may be at least as effective as a standard dose of 150 micrograms of thyroxine to treat endemic goitre in an iodine deficient area.

Seven hundred and fifty-one initially nondiabetic relatives of diabetic persons, in whom oral glucose tolerance tests (OGTT) have been performed, were followed for over 10 yr. Of these, 11.6% have died and no information was available from 13.7%. All other subjects were either retested (N = 369) or answered by questionnaire whether they are being treated for diabetes (N = 32) or not (N = 155). For test evaluation the sum of the 1- and the 2-h values during OGTT was used. The diagnosis of “diabetes” after 10 yr was made if the sum exceeded 500 mg/dl, which in 88% of cases coincides with fasting blood glucose values above 120 mg/dl. Among the retested individuals the results of OGTT showed a high degree of variation in both directions, which seems to represent just random variance rather than improvement or deterioration of biologic significance. These random changes in glucose tolerance do not correlate with changes in body weight. Sixty-three individuals have developed overt diabetes within the 10 yr. To optimize the discriminating value of the initial tests, the criteria dividing impaired glucose tolerance (IGT) from “normal” have been varied by a computer program. Sensitivity and specificity of the diagnosis IGT with respect to later development of diabetes depend on the criteria used and are inversely related. At the point where sensitivity and specificity are equal, both amount to 45%, and their sum never exceeds 90%. Using the criteria for IGT and diabetes recently proposed by members of an expert committee at the NIH, which are mainly based on the 2-h value and the fasting value, a sensitivity of 66% and a specificity of 19% are found. Thus, although a higher tendency toward the development of overt diabetes can be observed in the group of subjects with IGT compared with normal subjects, the prognostic value of the OGTT is very low when applied to individuals.