Hormonal steroids, neurotransmitters and sexual differentiation of the brain.
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Biomedical subjects
Publications and source records attributed to G Dörner.
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By well organized preventive examinations early tumour stages can be recognized. The diagnosis of prostatic cancer has to be secured by biopsy. The primary reliability of aspiration biopsies (cytology) was 94% compared with punch biopsies (histology) amounting to 73%. Indications and results of aspiration biopsies, radiological and nuclear medical techniques in diagnosing prostatic cancer are described. The combined anti-androgenic hormonal therapy (infusions of cytonal, subcapsular orchiectomy, permanent administration of oestrogen) is considered to be the unchanged basis of treatment. Comparative cytologic investigations in therapy indicate that high-voltage treatment connected with hormonal therapy seems to be superior to exclusive hormonal treatment. Observations after additional therapy by a radionuclid (89-Strontium) for affecting metastases are encouraging. Indications of a therapy by cytostatica in progressive prostatic cancer are explained.
Ethinylestradiol sulphate (J 96) is a depot estrogen which in a dosage of 2 mg per week has clearly antigonadotropic effects and evokes a suppression of the free testosterone in bilaterally orchiectomized patients with carcinoma of the prostate. The good compatibility in oral application and the possibility for the controlled intake recommend its use for the long-term therapy of the carcinoma of the prostate.
A radioimmunoassay of LH-RH with a sensitivity of 7.8 pg/ml is described. Labelling and purification techniques, methods for extraction of LH-RH and separation techniques of bound and free labelled hormone are compared. Determination of LH-RH levels in serum after administration of synthetic LH-RH by different routes and measurements of endogenous LH-RH levels in serum of normal subjects and patients with different endocrine diseases as well as in cerebrospinal fluid of normal men are performed. The measurement of exogenously administered LH-RH in serum reflects the disappearance of synthetic LH-RH from peripheral circulation in dependence upon the kind of administration route. The level of endogenous LH-RH was found to be under the limit of the assay in all samples of cerebrospinal fluid and of serum of normal male subjects. The results obtained in the patient groups show that the radioimmunological estimation of endogenous LH-RH in peripheral body fluids does not reflect the hypophysiotrophic role of this hypothalamic peptide.
Lactation was found to be significantly inhibited by greater than or equal to 2.0 mg methylergometrin-bimaleinate administered during the early postpartal period, particularly when the treatment was started as early as on the first or second day of puerperium. Therefore, such ergometrin treatment should be avoided as far as possible in order to improve breast-feeding, which was shown to be of great importance for the mental, psychic and physical development of the newborn.
A radioimmunoassay without chromatography was used for the determination of plasma aldosterone in pregnancy. The mean values (+/- S.D.) of aldosterone concentration increased consistently from 23.2 +/- 5.3 ng/100 ml (n = 14) during the first trimester to 37.2 +/- 10.6 ng/100 ml (n = 17) during the second trimester and 64.0 +/- 18.8 ng/100 ml (n = 29) during the third trimester of pregnancy. The highest values were found at delivery (71.9 +/- 14.2 ng/100 ml; n = 21) and in the cord plasma of newborns (83.4 +/- 14.9 ng/100 ml; n = 21). Significantly lower plasma aldosterone values were found in the plasma of pre-eclamptic women during the third trimester of pregnancy (41.9 +/- 21.3 ng/100 ml; n = 11).
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Experiments were performed in rats to study the role played by ovarian estrogens, the hypothalamus, the medicortical amygdala, and the ventral hipopcampus in the neurohormonal control of female sexual maturation. The results obtained demonstrated that the ovulation-inducing effect of a single administration of estradiol benzoate (EB) to immature female rats is not tantamount to the induction of precocious puberty. Long-term treatment with very low doses of EB, however, can accelerate sexual maturation, although it was established that the endogenous ovarian estrogen secretion during prepuberal life is not essential for the maturation of the cyclic ovarian function. Implantation of very low quantities of EB into the mediobasal hypothalamus of ovariectomized immature and postpuberal female rats revealed that the hypothalamic sensitivity to the LH-inhibiting effect of estrogen exhibits a gradual decrease that begins some days prior to the onset of puberty. It may be responsible for a temporary elevation of the LH level in the blood triggering final maturation of the ovarian follicles and an increase of estrogen secretion. - Studies on the influence of the limbic system on female sexual maturation lead to the following conclusions: 1. The mediocortical amygdala has an essential function in the maturation of the positive estrogen feedback. 2. An LH-inhibiting activity not related to the negative estrogen feedback is exerted by this nuclear region during critical periods of sexual maturation. It may form an additional protective mechanism against precocious stimulation of the ovaries. 3. By means of its stimulatory action on growth hormone and FSH secretion, the ventral hippocampus may be involved, by cholinergic mechanisms, in the interrelationships between metabolism and the onset of female puberty. The results which suggest a significant role of the limbic system in the control of female sexual maturation will be discussed with regard to recent data obtained in girls and women.
Total and free cortisol and cortisol binding globulin (CBG) levels were measured in plasma of 7 fetuses during 22 to 34 weeks of pregnancy and 80 infants aged 1 day to 30 months. In comparison with normal adults, total cortisol levels were significantly diminished (p less than 0.001) both in fetuses and newborn infants aged 2 to 8 days. However, low total cortisol levels were accompanied by extremely low CBG concentrations especially in prenatal but also in early postnatal life. Consequently, free cortisol levels during pre- and postnatal life were not significantly different from those of normal adults except the values immediately after birth, which were evidently elevated. With advanced age of the infants CBG values increased and reached the mean values of adults at 46 to 80 days of age. However, in infants aged 8 to 30 months CBG values were even significantly higher (p less than 0.01) than those of adults.
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Male sexual behaviour was found to be permanently decreased in neonatally reserpinized or paragylinized male rats. On the other hand, hypoplasia of sex organs was only observed in reserpinized, but not in pargylinized newborn males. Furthermore, male sexual behavior was found to be permanently increased in neonatally pyridostigminized males which showed even a slight hypoplasia of seminal vesicles in neonatal life. These findings suggest that changes of neurotransmitter concentrations and/or turnover rates apparently induced by psychotrophic drugs can affect sex-specific brain differentiation by direct action without mediation of sex hormones. Hence, neurotransmitters may be regarded as organizers of the brain.
To study the mode of action of oestrogen in female sexual maturation, prepubertal female rats were treated in different ways with oestradiol benzoate (OB). Using an improved implantation method, former findings on a hypophysial site of oestrogen action in the positive feedback (Hohlweg effect) were confirmed. A single s.c. injection or intrahypophysial implantation of OB at 25 or 26 days of age induced precocious vaginal opening (VO) and one ovulation, but the subsequent ovarian cycle was significantly prolonged, so that the first spontaneous ovulation occurred only at the normal time of the onset of puberty. Further studies demonstrated that the sensitivity to the ovulation-inducing effect of oestrogen increases as the rats approach the age of puberty, and that the first pubertal ovulation can be suppressed by intrahypophysial, but not by intrahypothalamic implantation of progestereone. The conclusion is drawn that the precocious induction of one ovulation via the Hohlweg effect is not tantamount to an advancement of puberty. The results furthermore suggest that the positive oestrogen feedback forms the basis for the first pubertal ovulation as it does with regard to later cyclic ovulations. True acceleration of sexual maturation was achieved by daily injections of 0,05 microgram OB/100 g b.w. from 5 days of age to VO. In contrast to findings obtained by other authors in Sprague-Dawley rats, a shortened OB treatment from 26 days of age to VO was not effective in advancing the onset of puberty unless the rats had additionally been injected with OB from 5 to 10 days of age. A final experiment demonstrated that the first ovarian cycle was not prolonged after neonatal ovariectomy and implantation of ovaries at 24, 28 or 32 days of age. Thus, maturation of the neurohormonal mechanisms that are responsible for the cyclic ovarian function continues during the prepubertal development in the absence of ovarian steroids.
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Changes in neurotransmitter concentrations, which are brought about by the administration of neurotropic pharmaceuticals to albino rats at the time of differentiation of the brain, may have a lasting effect upon the reactivity and adaptability of adult animals to environmental factors and give rise to specific patterns of behavior. 1. Pargyline, when administered neonatally, resulted in a reduction of learning power, decrease in the power of retention, as well as reduction of the decision-making ability. 2. Reserpine gave an improvement of learning power, but simultaneously decreased both the power of retaining what had been learnt and the decision-making ability. 3. Pyridostigmine gave a marked improvement of adaptability which was evidenced in higher learning power, greater retentiveness, and better decision-making ability.
Immature and postpuberal female rats were ovariectomized at 20 or 27 days of age or on the day of the first vaginal oestrus and chronically implanted with oestradiol benzoate (OB) and cholesterol at the ratios of 1 : 60, 1 : 120 or 1 : 240 on the day following castration. Autopsy was performed on day 6 after implantation and the plasma LH concentration determined by radioimmunoassay. Whereas 1 : 60 and 1 : 120 implants of OB and cholesterol placed into the hypothalamic ventromedial-arcuate region depressed the castration-induced elevation of the LH level before and after puberty, the 1 : 240 mixture was effective only in immature rats, but not after vaginal opening and the first ovulation had occurred. A similar trend was recorded after implantation of OB into the cortical amygdaloid nucleus (CAN). However, the oestrogen dose had to be doubled to get comparable results. Bilateral lesioning of the CAN or deefferentation of the mediocortical amygdala by transection of the stria terminalis did not distinctively influence the LH-suppressing effect of daily s.c. injections of 0.1 or 0.05 microgram OB/100 g b. w. in prepuberal rats. The findings demonstrate a sudden change in the hypothalamic threshold to the gonadotrophin-inhibiting effect of oestrogen over a narrow range of time near the onset of puberty. They furthermore suggest that the mediocortical amygdala is not involved in possible extra-hypothalamic control of the puberal desensitization process.
A non-chromatographic competitive binding assay (CBA) using horse transcortin has been employed in the routine measurement of cortisol in plasma, urine and amniotic fluids. Comparing the values with those of a radioimmunoassay (RIA) or a fluorimetric method (FM) an excellent correlation between the three methods both in plasma and urine has been calculated in normal subjects and in patients with various endocrine disorders. In amniotic fluids, however, there were discrepancies between CBA and RIA. Whereas CBA showed no differences, RIA gave significantly higher values in amniotic fluids of female than of male fetuses. Elevated free plasma cortisol levels observed in patients with prostatic cancer after diethyl stilboestrol diphosphate therapy did not correlate with unconjugated urinary cortisol concentration as measured with CBA and FM. In newborns, a relatively high plasma level found 12 hours after birth was followed by a nadir on the 2nd and 3rd day of life and by an increase until levels of adults on the 5th day of life were reached.
Qualitative dysnutrition (pure bottle-feeding) as well as quantitative dysnutrition (overnutrition as well as undernutrition) during the first trimenon of postnatal life was found to lead to long-lasting mental, psychic and/or physical ill-effects in the human. Females who were completely bottlefed during neonatal life showed significantly decreased school achievements as well as significantly decreased learning capacity and social adaptability at 16 years of age as compared to females who were purely breastfed or breast- plus bottlefed in neonatal life. Males who were artificially overfed during neonatal life also showed significantly decreased school achievements and significantly decreased learning capacity in adolescence as compared to males with normal weight development in neonatal life.
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