Biomedical subjects
Publications and source records attributed to G Dörner.
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Men who were born in war and post-war periods with shortage of food supply (1943-47) showed a markedly low prevalence of insulin-treated diabetes mellitus (ITDM), but not of non-insulin-treated diabetes mellitus (NITDM) in later life. A significant increase (+54%) of ITDM prevalence was observed between 1976 and 1982 for subjects at 26-31 years of age, who were born in a post-war period (1945-50) with shortage and a peace period (1951-56) without shortage of food supply, respectively. By contrast, there was not found an increase--but even a slight decrease (-14%)--of ITDM prevalence between 1976 and 1982 for subjects at 38-43 years of age, who were born in a peace period (1933-38) without shortage and a war period (1939-44) with shortage of food supply, respectively. A similar clear dependence of diabetes prevalence on food supply in perinatal life could not be observed for NITDM. On the other hand, the prevalence of NITDM appeared to be significantly dependent--in contrast to ITDM--on food supply in adulthood.
Several experimental and clinical findings suggest that different sex hormones (oestrogens and/or androgens) are responsible for sex-specific brain differentiation of gonadotrophin secretion, sexual orientation and gender role behaviour.
The effects of perinatal sexual differentiation of the brain and of postpuberal sex hormone levels on the development of sex-specific differences in body weight as well as triglyceride (TG), high-density-lipoprotein-cholesterol (HDL-CHOL) and total cholesterol were investigated. Significant differences in body weight of male and female rats are attributed to the influence of different androgen levels during the perinatal period as well as to the influence of different postpuberal estrogen (E) and androgen (A) levels. Sex-specific differences in TG serum levels are essentially caused by varying influence of androgens during the perinatal period, possibly in part after conversion to estrogens. Different postpuberal sex hormone concentrations seem to have only little effect on the TG levels. Sex-specific differences in HDL-CHOL serum levels appear to be independent of androgens during the perinatal period as well as of physiological postpuberal estrogen levels. These differences are mainly the result of the current postpuberal androgen levels. Total CHOL did not show any sex-specific differences under the conditions of the experiment.
A highly significantly decreased prevalence of insulin-dependent childhood-onset diabetes (less than 1/3 of the initial prevalence rate) could be achieved in Berlin/GDR since 1973 by improving systematically diagnostic and therapeutic measures for pregnant diabetics, particularly for non-insulin-dependent gestational diabetics. In addition, a highly significantly increased incidence rate of diagnosed, diet-treated and delivered non-insulin-dependent pregnant diabetics was found between 1979 and 1983 in Berlin/GDR, Halle and Leipzig as compared to the other districts of the GDR. Simultaneously, a highly significantly decreased prevalence rate of diabetic children (less than 1/3), who were born during this period, was found in 1983 for Berlin, Halle and Leipzig as compared to the other districts of the GDR. Finally, a highly significant inverse correlation could be demonstrated for the 15 districts of the GDR between the incidence rates of diagnosed, diet-treated and delivered non-insulin-dependent pregnant diabetics and the prevalence rates of diabetic children who were born during this period (1979-1983). In view of these findings, an interruption and even a reversal of the continued dramatic increase of idiopathic insulin-dependent diabetes mellitus appears to be possible in the developed countries by preventing maternal hyperglycaemia during pregnancy and hence hyperinsulinism in the foetuses and newborns.
To examine the question if an endogenous oestrogen-independent rhythm is involved in the cyclic variation of sensitivity to the negative feedback of oestrogen recorded in a former study, adult female rats were ovariectomized on subsequent days of a 4-day ovarian cycle, injected with 3 micrograms oestradiol benzoate (OB)/100 g b.w. or oil three days after castration, and autopsied on the following day. Estimation of the serum LH concentration revealed a similar LH-inhibiting effect of OB in all experimental groups. Female rats were then implanted with OB or cholesterol in the medial preoptic area (MPOA) in metoestrus. In part of the rats, the implants were removed on the presumptive day of pro-oestrus to imitate the periovulatory decline of the circulating oestrogen level acting on the MPOA. Evaluation of the sensitivity to the negative oestrogen feedback during oestrus and metoestrus demonstrated that s.c. injected OB was highly effective in suppressing the LH secretion after removal of the OB implants in pro-oestrus, but not in rats with the implants left in place till autopsy. In a final experiment, the pro-oestrous progesterone surge was inactivated by the injection of specific antibodies. An influence of this treatment on the LH-inhibiting effect of OB examined during oestrus and metoestrus could not be found. Taken together the results suggest that the high sensitivity to the negative oestrogen feedback recorded during the postovulatory period in cyclic female rats is mainly induced by the periovulatory fall of the circulating oestrogen level leading to reduction of the medial preoptic oestrogen concentration.
Ethinylestradiol sulfonate (Turisteron) is an orally highly active depot-estrogen with relatively low side effects. In men with prostatic cancer, weekly administration of 2 mg Turisteron resulted in a striking decrease of the biologically active free testosterone level to less than 2% of the basal level; i.e., even significantly lower than after orchidectomy. Turisteron was able to normalize the 5 year survival rate in men with advanced non-metastatic cancer (T3NxM0) and to increase the survival rate significantly in men with metastatic cancer (T3-4, Nx, M1). Hence, due to our experience, Turisteron treatment is a very effective, non-expensive and well tolerated therapy for prostatic cancer.
Damage to the medial preoptic area (MPOA) was produced in one-day-old female rats by bilateral electrolytic lesions or by aspiration of preoptic tissue. Both procedures resulted in similar advancement of vaginal opening and the first ovulation. A further group of rats was lesioned or aspirated in the MPOA and immediately bilaterally implanted with medial preoptic tissue collected by the puncture method from 17-19-day-old female rat fetuses. After autopsy, tissue destruction and implants located in the MPOA could be identified in 5 females that showed significantly later onset of puberty than both the lesioned or aspirated and the untreated controls. The findings suggest that the elimination of neurones and not a stimulatory effect of electrolytic lesions on GnRH secretion is responsible for the acceleration of sexual maturation recorded after lesioning of the MPOA. Possible reasons for the failure to identify the grafts in most of the implanted females are discussed.
The effect of pargyline on 5 HT concentration in a combined forebrain and midbrain section ( FMB ) have been investigated in female rats which were temporarily deprived from their dams in postnatal life and daily injected with the monoamine oxidase inhibitor. Two hours after the last pargyline injection a marked increase in 5 HT concentration could be observed both in 12 and 30 days-old rats. The question is raised whether 5 HT may be involved in neuroendocrine mechanisms which are responsible for controlling the onset of puberty, since a significant advance of puberty could be achieved by this pargyline treatment in normal and deprived female rats.
Groups of female rats were autopsied at daily intervals from 27 days of age through the first vaginal cycle and the serum FSH and LH and plasma estradiol-17 beta (E2) concentrations were estimated. Fluctuating hormone concentrations were recorded between days 27 and 31. Both gonadotropins and E2 dropped to a very low level on days 32 and 33 and showed then a progressive increase that commenced on day 34 and terminated for LH and E2 on day 39, i.e. in proestrus, whereas FSH declined from day 37 to day 39. The circulating gonadotropin level was lower during the first postpubertal diestrus than during most of the prepubertal phase. The findings suggest that a high sensitivity to the gonadotropin -inhibiting effect of estrogen prevented completion of an ovarian cycle up to day 33. After that, desensitization to the negative estrogen feedback as indicated by the simultaneous rise of E2 and gonadotropins makes final maturation of ovarian follicles and the first ovulation possible. In part of the rats aged 27-38 days cell nuclear volumes of medial preoptic neurons were evaluated, because recent results suggest that estrogen induces the desensitization process by an inhibitory action on the medial preoptic area. In accordance with this assumption, an inverse relationship between nuclear size and the E2 level in the blood could be revealed.
Female rats were ovariectomized at 31 days of age, on the day of proestrus, or on the day of the first vaginal estrus if corpora lutea were seen in the ovaries. Immediately after castration, estradiol-17 beta (E2) or oil was administered via s.c. silastics capsules, or a 1:240 mixture of estradiol benzoate (EB) and cholesterol or cholesterol alone was unilaterally implanted into the hypothalamic ventromedial-arcuate region. Forty-eight hours after surgery the rats were decapitated and the serum concentrations of LH and FSH estimated. In rats implanted s.c. with E2 in anestrus, proestrus or estrus, estrogen treatment reduced the circulating LH level to 9.4; 60.4 and 33.6% and that of FSH to 49.5; 120.3 and 63%, respectively, of the concentration recorded in the corresponding controls implanted with oil. Following the intrahypothalamic implantation of EB, the serum concentration of LH was lowered to 20.8; 67.4 and 68.1% and that of FSH to 48.8; 87.0 and 62.0% as compared to the cholesterol-implanted controls. The findings clearly suggest that a major part of the change in sensitivity to the negative feedback of estrogen occurs prior to the first preovulatory surge of gonadotrophins.
Immature female rats were bilaterally lesioned in the medial preoptic area (MPOA) or hypothalamic ventromedial-arcuate region (VMAR) at 21 days of age and daily injected with the dopamine (DA) agonist bromocriptine (CB-154) through day 26. Estimation of the serum LH and FSH concentrations following ovariectomy and two injections of 0.05 micrograms oestradiol benzoate (OB)/100 g b.w. revealed that the desensitization to the negative feedback effect of OB induced by lesioning of the MPOA was almost completely prevented by CB-154. A similar effect of the drug was not found in rats lesioned in the VMAR. The DA antagonist alpha-methyldopa (alpha-MD) was then bilaterally implanted in the MPOA or VMAR of 28-day-old females. Evaluation of the gonadotrophin-inhibiting effect of OB on days 30-31 showed that medial preoptic, but not hypothalamic implants of alpha-MD reduced the sensitivity to the inhibitory action of OB. It is proposed that diminution of the dopaminergic activity in the MPOA may play a role in the prepubertal desensitization to the negative oestrogen feedback in female rats.
A sensitive enzyme immunoassay for cortisol in plasma and saliva without extraction has been developed. An antibody was raised in rabbits against cortisol-3-CMO-BSA and compared with anti-cortisol-21-HS-HSA. The enzyme label was a covalently linked cortisol-horseradish peroxidase conjugate. Solvent extraction was avoided by use of heat denaturation of transcortin and dilution of plasma 1:300. This assay had a limit of detection of 3 fmol/tube and satisfied the standard criteria of accuracy and precision. The test requires only a simple photometer. The normal values of cortisol in plasma and saliva before and after ACTH, dexamethasone or metyrapone application were determined. Saliva, being easily collected by a noninvasive, stress-free technique is an alternative to plasma. The cortisol concentrations were significantly increased in plasma and saliva of patients with Cushing's syndrome and decreased in patients with Addison's disease.
In order to investigate the possible influence of pre- and/or early postnatal nutrition on the development of diabetes mellitus in later life, diabetes prevalences were ascertained in subjects of similar ages who were born in different periods with or without shortage of food supply. Between 1974 and 1982 the total prevalence of diabetes mellitus increased in Berlin/GDR by 26%. A significantly higher increase of diabetes prevalence (approximately 90%) was found between 1974 and 1982 for subjects at 26-33 years of age, whose years of birth changed from a "hypocaloric war and post-war period (1941-1948)" to a "relatively hypercaloric peace period (1949-1956)". By contrast, there was not found any significant increase of diabetes prevalence between 1974 and 1982 for subjects at 34-41 years of age, whose years of birth changed from a "relatively hypercaloric period (1933-1940)" to a "hypocaloric period (1941-1948)". These findings give further evidence for the dependence of diabetes prevalence in later life on nutrition in perinatal life.
In view of experimental and clinical findings, it was predicted (Dörner, 1973 and 1976; Dörner and Mohnike, 1973 and 1977) that a preventive therapy of diabetes mellitus may be possible by preventing hyperinsulinism in perinatal life by means of prevention of hyperglycaemia in pregnant women and overnutrition in newborns. Meanwhile, this prediction appears to have been realized. Thus, the prevalences of diabetes mellitus in children, who were born in Berlin/GDR over the past decade, were found to be significantly decreased as compared to those born between 1962 and 1972. On the other hand, the children born in Berlin/GDR between 1962 and 1972 displayed a significantly higher prevalence of diabetes mellitus as compared to those born between 1957 and 1961. The decreasing prevalence of childhood-onset diabetes over the past decade has been apparently achieved by systematic prevention of hyperglycaemia and impaired glucose tolerance in pregnant women and overnutrition in newborns. These findings suggest that a preventive therapy of diabetes mellitus--even of insulin-dependent childhood-onset diabetes--is possible by preventing hyperinsulinism in the foetus and newborn during differentiation and maturation of the neuroendocrine central nervous-pancreatic system.
The present investigation examined the relationship between concentrations of plasma proteins in oestrogen-primed adult rats and sex hormone concentrations in neonatal life. alpha 2-acute phase globulin (alpha 2-AP) and female specific protein (FP) were found to be higher in adult females than in adult males. Androgen administration in females on the first day of life declined permanently these protein concentrations, while neonatal castration in males on the first or third day of life resulted in a permanent increase in FP concentration. Both the alpha 2-AP and FP response in adulthood to hormonal stimulation is dependent on the androgen level during a critical neonatal organization period.
A radioimmunoassay (RIA) for testosterone (T) was found to be suitable for determination in plasma of rats. Since the cross-reactive dihydrotestosterone levels were extremely low both in males (130.8 +/- 27.6 pmol/l) and females (189.4 +/- 41.3 pmol/l), the procedure measured T equally well, whether or not chromatography preceded the RIA. The method met all requirements of precision, sensitivity, accuracy and specificity. Basal levels of 5 male control groups (n approximately equal to 10) showed considerable variations from a low of 6.86 +/- 4.68 nmol/l to a high of 16.26 +/- 5.06 nmol/l. This high variability may be the reason, at least in part, for the fact that moderate stress did not produce always a significant decrease of T levels in males. However, after forced stress or administration of adrenaline plasma T was significantly (p less than 0.01) lower than in controls. Gonadectomy lowered extremely plasma T levels both in males and females, whereas adrenalectomy had no significant effect. These data demonstrate that the gonads are the main sources of T in both sexes. The significant (p less than 0.01) decrease of T levels after administration of adrenaline, dexamethasone and ACTH in adrenalectomized males indicated that these substances affect mainly the testicular synthesis of T. In cyclic females, administration of ACTH produced no significant change in plasma T levels. During pregnancy, there was a significant (p less than 0.01) increase of plasma T values from day 10 to day 18-19, followed by a decrease to day 22.
Maternal deprivation from the 3rd to 14th day of life, i.e., separation of the pups from their mother animals for 16 hours each day, gave rise to persistent significant changes of microstructures in the hippocampal stratum radiatum of the CA1-region, which were associated with significantly decreased emotionality, learning capability and memory capacity in adulthood. Such teratomorphogenic effects on the brain produced by psychosocial and/or nutritional deprivation during brain development could be partly prevented--as well as the teratophysiogenic and teratopsychogenic effects--by simultaneous administration of the acetylcholinesterase inhibitor pyridostigmine.