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Biomedical subjects

F Leidenberger

Publications and source records attributed to F Leidenberger.

At least 19 recordsLinked to original sources
PubMed1996

The antibodies causing thyroid stimulating hormone-binding inhibition (TSH-BI) are not responsible for the specific inhibition of gonadal steroidogenesis by Graves' sera.

Graves' disease is attributed to the presence of autoantibodies with agonist activity which interact with the TSH receptor causing thyroid hyperstimulation and hyperthyroidism. The degree of TSH-binding inhibition (TSH-BI) caused by a Graves' serum in a TSH radioligand receptor assay is considered to be an index of the prevalence of anti-TSH receptor autoantibodies in that serum. We have previously shown that the specific inhibition by Graves' serum of hCG-stimulated steroidogenesis by Leydig cells was at a site distal to receptor binding and second messenger activation. In this report, we have investigated whether the effect of Graves' serum upon Leydig cells is a property of the constitutive antibodies. Immunoglobulin-enriched fractions were obtained from Graves' and normal sera using three increasingly rigorous procedures; ammonium sulphate precipitation, caprylic acid treatment and Protein A or G-affinity purification. The TSH-BI was determined for untreated and extracted sera in two radioreceptor assays developed for use with serum, one using human thyroid membranes and the other using HeLa cells transfected with the human TSH receptor, and the results were compared with effects in the Leydig cell steroidogenesis bioassay. The specific inhibition of hCG-stimulated Leydig cell steroidogenesis by Graves' sera was not retained in the antibody fraction causing TSH-BI. Thus, the inhibitory factor appears not to be an antibody and we are now attempting to purify and identify the responsible factor from Graves' serum.

Ammonium Sulfate↗
PubMed1996

Investigation of the influence of two low-dose monophasic oral contraceptives containing 20 micrograms ethinylestradiol/75 micrograms gestodene and 30 micrograms ethinylestradiol/75 micrograms gestodene, on lipid metabolism in an open randomized trial.

An open comparison at a single center was performed in volunteers (n = 58) randomly allocated to two treatment groups, one receiving tablets containing 20 micrograms ethinylestradiol (EE) + 75 micrograms gestodene, and the other 30 micrograms EE + 75 micrograms gestodene. The study consisted of three treatment-free pre-cycles, followed by thirteen 28-day treatment cycles. Analysis of results revealed that there were no statistically significant differences between the two groups with regard to the plasma levels of HDL-cholesterol and its subfractions, LDL-cholesterol and apolipoproteins. There was, however, a trend toward a more favorable effect on HDL-cholesterol in the 20 micrograms EE group, where levels increased by 3% compared with the 30 micrograms EE group, where levels decreased by 9%. There was a statistically significant difference between the adjusted mean values of total triglycerides in the two groups in favor of the 20 micrograms EE group (+21%), compared with the 30 micrograms EE group (+64%) (p = 0.029). Two serious adverse events were reported (lymphadenopathy and vertigo), but neither were considered to be causally related to either study medication. The formulation containing 75 micrograms gestodene and 20 micrograms EE was shown to be a reliable and well tolerated oral contraceptive, with a favorable lipid profile.

Adolescent↗
PubMed1993

Graves' autoimmune serum inhibits gonadal steroidogenesis: development of a Leydig cell bioassay to identify broad spectrum anti-endocrine autoantibodies.

In order to establish an assay for the detection of autoimmune sera with broad spectrum activity, we have investigated the effect of unselected normal and Graves' disease sera upon steroidogenesis by gonadal cells. Steroidogenesis was enhanced by the addition of normal serum in a 3-h primary Leydig cell bioassay, but was inhibited by the majority of Graves' sera. The inhibition was not related to clinical thyroid parameters, such as the severity of the TSH-binding inhibition index, and was not overcome by other agonists or second messenger supplements. Although pituitary TSH preparations bound to and stimulated Leydig cells, TSH receptor mRNA was not detectable and pure recombinant TSH failed to bind or stimulate, indicating contamination of pituitary TSH with LH. The binding of hCG to the Leydig cell luteinizing hormone receptor was not perturbed by the Graves' autoimmune sera, indicating that cross-reactive anti-TSH receptor antibodies were not responsible for the inhibition. By use of intermediates in the stimulatory pathway, the site of Graves' serum inhibition was identified to be distal to hormone receptor/adenylate cyclase coupled responses and proximal to supply of cholesterol for steroidogenesis.

Animals↗
PubMed1993

Serum unmasks the binding of thyroid-stimulating hormone to endogenous and transfected receptors: evidence for a soluble form of the receptor in human thyroid.

A specific homologous radioligand receptor assay for thyroid-stimulating hormone (TSH) using bovine thyroid membranes was adapted for use with human thyroid. Specific 125I-labelled TSH binding was detected in the 3000 g membrane pellet from bovine thyroid but predominantly in the 3000 g supernatant of the human thyroid homogenate. Both assays required incubation in the presence of 10% serum, whilst the assay using human thyroid could only be precipitated using polyethylene glycol (PEG). The serum requirement transcended a possible role as carrier protein and unmasked specific TSH binding. Molecular sieving determined that the active fraction of the serum had an apparent size of 30,000-100,000. The requirement for PEG-assisted precipitation of the TSH receptor assay was a consequence of the TSH-binding entity from Graves' thyroid behaving like a soluble 'receptor': it did not sediment with the membranes, passed a 0.2 microns filter and, upon molecular sieving, had an apparent size of 300,000-1,000,000. A full-length TSH receptor cDNA was cloned from a human Graves' thyroid library and stably transfected cell lines expressing the TSH-receptor protein were constructed using human HeLa and murine 3T3 cells. Specific TSH binding was unmasked by serum in the human cell lines, as observed for the human thyroid TSH receptor, whereas serum hindered TSH binding in the murine cell lines. A soluble form of the receptor was not released from the cells and was not produced in conditions which demonstrated a soluble receptor-like binding component in human thyroid tissue.

Animals↗
PubMed1991

[Rational hormone diagnosis in normocyclic functional sterility].

Functional infertility in women with a normal menstrual cycle is the first symptom of a pathophysiological sequence of multiple different endocrinopathies. It usually progresses and leads to secondary amenorrhoea which is the most severe symptom of ovarian insufficiency. The percentage of abnormal hormonal parameters will increase with the duration and extent of the endocrinological aberration. The aim of this study is to examine the frequency of the different potential changes in hormone levels of an unselected group of female patients in a fertility clinic. 307 patients suffering from functional sterility (menstrual cycle 25-34 days) were investigated via basal hormone laboratory tests (including TRH test) under standardised conditions. 73 patients had pathological changes of the Fallopian tubes and in 116 patients their husbands had severe andrological problems. Excluded from this study were patients with bilateral occlusion of the Fallopian tubes and patients whose partners had a sperm count of less than 1 million/ml. The percentage of abnormal hormone levels (greater than mean + standard deviation + grey area) was 32.2% for prolactin (PRL), 7.8% for TSH, 20.9% for Delta-TSH, 18.4% for DHEA-sulfate (DS), 9.8% for testosterone (T), 18.9% for LH, and 11.5% for FSH (LH and FSH were specifically calculated only in 87 patients). In 65.5% of the patients the midluteal oestradiol (E2) and progesterone (P) levels were below normal, as sign of a corpus luteum insufficiency (CLI). A step- by-step diagnostic procedure would have yielded the following cumulative abnormal hormone levels retrospectively: (1) PRL (n = 99) = 32.2% (2) +TSH/delta TSH (n = 85) = 48.9% (3) +DS (n = 56) = 58.0% (4) +T (n = 30) = 59.3% (5) +LH/FSH (n = 28) = 62.2% [(6) +E2/P (n = 201) = 82.7%.] Only in 37.8% (116 patients) all hormone levels were within normal limits during the early follicular phase (FP); if the patients with signs of CLI are added, the percentage would be only 17.8% (n = 53). Case analysis demonstrated that functional sterility was accompanied by hyperprolactaemia in 32.4% of all patients, by abnormalities of the thyroid function (hypothyroidism 16.0%, hyperthyroidism 7.8%) in 23.8%, by hypothalamic and/or pituitary dysfunction in 28.7%, and by hyperandrogenaemia in 22.5%. Primary ovarian insufficiency was diagnosed in 4.6%. 31.3% of all patients (n = 307) had a combination of different hormonal abnormalities. The average duration of infertility among this group of patients was 6.3 years.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1990

Influence of melatonin on the sleep-independent component of prolactin secretion.

Sleep has a stimulatory effect on prolactin secretion. Recent studies in the human suggest the hypothesis that prolactin has also an endogenous sleep-independent rhythm, which can be influenced by endogenous melatonin. To investigate this hypothesis, the prolactin response to nighttime exposure to bright light was studied in eight women in detail. Light exposure induces a decrease in nocturnal melatonin secretion. It was demonstrated that exposure to bright light for 2 h at night caused a decrease in prolactin secretion, which surpassed significantly the decline one would expect by sleep deprivation only (P less than 0.01). This was associated with a similar decline in melatonin secretion. Fall and rise of prolactin secretion under these conditions were always preceded by decrease and rise in melatonin levels in all eight women studied. Based on these observations, it is concluded that melatonin is associated with an endogenous circadian component of prolactin secretion. As specific melatonin receptors have been identified in the human nucleus suprachiasmaticus, which is the "master" circadian pacemaker, the observed phenomenon might be mediated through this structure. An alternative explanation of our findings could be based on the fact that melatonin influences dopamine metabolism, which in turn alters prolactin secretion. It can also not be ruled out that melatonin might act via the opioid system, which then could affect prolactin secretion. The total secretory activity for both hormones (area under the curve) did not change under experimental conditions, when compared to a control group. This suggests that acute light exposure and sleep deprivation influence the secretory process rather than the synthesis of these two hormones. This is in agreement with the observation that changes in natural light exposure throughout the year do alter the amplitude, but not the total amount of melatonin secreted. Further studies are needed to answer the question of melatonin storage definitively, as it is commonly believed that melatonin is immediately released after synthesis. It is concluded that melatonin through its external modulator light might entrain the circadian sleep-independent component of prolactin secretion and via its action on prolactin could modulate reproductive processes.

Adult↗
PubMed1990

Circadian variations in plasma melatonin, FSH, LH, and prolactin and testosterone levels in infertile men.

Circadian patterns of plasma melatonin, FSH, LH, prolactin, and testosterone were studied in 10 healthy men, 20 men with oligozoospermia, and 8 men with azoospermia. Circadian rhythms were found in concentrations of melatonin and prolactin, with higher values at night in comparison with daytime levels. In patients with oligozoospermia and azoospermia an elevation in melatonin levels was observed, and an increase in melatonin concentrations occurred before onset of darkness (i.e., at 2000 h). Levels of FSH, LH, and prolactin were elevated in infertile patients. The possibilities that an increase in melatonin concentrations is either the primary feature that leads to the regression of the seminiferous epithelium or is secondary and depends on elevated gonadotropins and/or prolactin levels are discussed.

Adult↗
PubMed1990

[Endocrinological diagnosis of normocyclic functional sterility].

Normocyclic functional sterility can be regarded as a starting point to the common pathophysiology of different endocrinopathies. Those are finally leading to secondary amenorrhoea, as the most severe sign of ovarian insufficiency. The incidence of abnormal hormonal parameter increases parallel to the duration and the extent of the respective endocrinopathy. For a better causal classification of the endocrine disorder a complete hormonal assessment is mandatory, as characteristic historical data or significant clinical signs will often be missed in infertile patients. The completion of one single basic hormonal examination might lead to an exact differentiated diagnosis and then allows accordingly for the induction of a purposeful treatment. The pregnancy rates are considerably high proving the effectiveness of the thoughtful pretherapeutic diagnostic evaluation. The principle of cost-effectiveness is as well maintained by the follow-up of complete diagnosis and master-tailored therapy.

Androgens↗
PubMed1989

Functionally distinct agonist and receptor-binding regions in human chorionic gonadotropin. Development of a tertiary structure model.

The histidine residues in human chorionic gonadotropin (hCG) were chemically modified using diethyl pyrocarbonate. Derivatives of hCG with an average of 0.5-3.5 histidines modified (maximum of 4 per hCG) had reduced receptor-binding and cell-stimulating activities. Acylation of hCG at progressively lower pH values (conditions in which 1 of the 2 absolutely conserved histidines alpha His-83 is not titratable, whereas alpha His-94 becomes increasingly protonated and resistant to modification) produced hCG derivatives with a greater retention of receptor-binding activity than cell-stimulating activity. The involvement of alpha His-94 as part of the receptor-binding region of the hormone and of alpha His-83 as a putative active site residue was inferred. Proteinaceous protease inhibitors were shown to neutralize the agonist activity of hCG and to reduce the binding of hCG to its receptor and also to specific antisera. It was presumed that an inhibitor-hormone complex was formed which was analogous to the complexing of inhibitor with the "substrate pocket" of a serine protease. The discovery of primary sequence analogies between hCG and the serine protease chymotrypsin enabled the prediction of hCG structure using the enzyme as a folding template. Solvent-exposed and buried core regions of the peptide chain were delineated using smoothed hydrophobicity profiles in combination with Chou-Fasman secondary structure predictions. Hypervariable hydrophobicity indices between residues 38 and 80 of the human beta subunits reflected different folding arrangements which presumably conferred the individual receptor specificities. When mapped to the putative structure these receptor-determinant loops were adjacent to an area of the alpha subunit analogous to the substrate pocket of serine proteases. Disulfide bond assignments and intersubunit contact regions were identifiable. The proposed tertiary structure for hCG manifests the topographical epitopes defined using monoclonal antibodies and satisfies the currently available data on specific modification and its effects upon hormonal structure and function. This paper is considered to be the first report of a differential effect upon the agonist and receptor binding abilities of a glycoprotein hormone after modification of the proteinaceous, as opposed to the glycosylated, moiety of the molecule.

Amino Acid Sequence↗
PubMed1989

[Rational hormonal diagnosis of oligomenorrhea].

In a study, conducted by two clinics in Berlin and Hamburg, specializing in reproductive endocrinology, the anamnestic, clinical, and laboratory data of 170 oligomenorrheic patients (menstrual intervals between 35 and 90 days) were evaluated in order to determine the frequency of possible causes of oligomenorrhea. Pathological hormone levels were found in two thirds of all patients. The order of frequency of abnormal hormone levels was as follows: hyperandrogenemia (testosterone and/or DHEA-sulfate) in 41.8%, hyperprolactinemia in 25.9%, abnormal thyroid function (TSH and/or TRH-induced TSH) in 21.7%, and hypergonadotropic FSH levels in 3.5% of all patients. There was an overlap of between two or more pathological conditions in one third of all patients. This study confirms results of a previous study in amenorrheic patients (Moltz et al., 1987 - see reference list), documenting hyperandrogenemia as the most frequent abnormality found in this group, followed by hyperprolactinemia. As can be expected, the percentage of women with no discernible abnormality was higher in oligomenorrheic patients when compared with the amenorrheic group (32.3% vs 7.7%). Furthermore, overweight patients were overrepresented in the oligomenorrheic group, while underweight patients were seen more frequently in the amenorrheic group. In view of these results of our study we recommend a detailed diagnostic follow-up in all younger patients with ovarian disorders who need to preserve their reproductive potential. This follow-up should include hyperprolactinemia, hypo-/hyperthyroidism, hyperandrogenemic and hypoestrogenemic states and exclusion of primary ovarian failure. In contrast to recommendations of WHO, issued in 1976, such diagnostic work allows an etiology oriented therapy decision and a therapy risk assessment in subgroups of patients, such as hyperandrogenemic patients, who receive clomiphene or gonadotropin treatment. Furthermore, it permits prophylactic considerations, for prevention of hirsutism and polycystic ovarian disease, struma and osteoporosis prophylaxis.

Adolescent↗
PubMed1987

[Rational hormonal diagnosis of secondary amenorrhea].

The usefulness of the guideline recommended in 1976 by the World Health Organization (WHO) for the differential diagnosis of ovarian sterility needs critical reevaluation, since it does not take into account new aspects such as the pulsatility of GnRH secretion, androgen excess, or thyroid disorders and other phenomena related to ovarian dysfunction. In order to demonstrate the relative frequency of such phenomena, the authors examined 183 women with secondary amenorrhea of more than three months' duration (mean +/- SD = 12.7 +/- 18.4 months). The endocrine status of these women was examined under standardized conditions in two clinical endocrinology units in the cities of Hamburg and Berlin. The percentages of abnormal hormonal data (greater than mean +/- SD + gray zone) were as follows: testosterone (T) 39.9%; DHEA sulfate (DS) 29.5%; prolactin (PRL) 18.0%; TSH 11.5%; FSH or LH 26.8%; estradiol (E2) 30.1%. Among 96 patients with increased T and/or DS (52.5% of all patients), 53 patients (55.2%) did not show any clinical signs of androgenization (hirsutism, acne). Retrospective evaluation of all data revealed that a stepwise diagnostic procedure would have resulted in the following cumulative percentages of hormonal abnormalities: (1) T = 39.9%; (2) +DS = 52.5%; (3) +PRL = 60.2%; (4) +LH/FSH = 82.0%; (5) +E2 = 91.2%; (6) +TSH = 92.3%. Only in 7.7% of all patients were all hormonal parameters within normal ranges. Individual case analysis showed that 52.5% of all patients had hyperandrogenemia, while 18% had hypothalamic amenorrhea without any other pathologic condition; 17.5% had hyperprolactinemia and 3.3% primary ovarian insufficiency. Another 4.9% had hypothyroidism only, while 1.1% had exclusively hyperthyroidism. Combined hormonal deviations were found in 24% of all patients. Considering the differential diagnosis of secondary amenorrhea from an economic point of view, one comes to the conclusion that direct and indirect expenditures are similar in magnitude, no matter whether one prefers a conventional stepwise procedure or a one-step hormonal analysis encompassing all potentially relevant hormones (DM 859.00 + 10 weeks waiting time vs. DM 827.50 + 1 week waiting time). Androgen excess is much more frequent than was believed; hirsutism and/or acne by no means necessarily occur in cases of androgen excess. Hyperprolactinemia is less frequent than hyperandrogenemia. Thyroid status should be evaluated in all women with functional amenorrhea. The stepwise diagnostic procedure as recommended by the WHO is time-consuming, complicated, and sometimes incomplete in the diagnostic work-up, with obvious potential disadvantages for therapy.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1986

Human placental lactogen and unconjugated estriol concentrations in twin pregnancy: monitoring of fetal development in intrauterine growth retardation and single intrauterine fetal death.

Human placental lactogen and unconjugated estriol concentrations in maternal serum were evaluated in 100 uneventful twin pregnancies, and these values were compared with those observed in 16 twin pregnancies associated with intrauterine growth retardation or single intrauterine fetal death. In pregnancies associated with intrauterine growth retardation (n = 8), human placental lactogen levels were at the lower limit of normal range for singleton pregnancies, whereas estriol levels were normal in most cases. When one of the fetuses had died before week 33 of pregnancy (n = 5), both human placental lactogen and estriol levels were low and they were almost at the levels in singleton pregnancy. When intrauterine fetal death occurred after week 36 of pregnancy (n = 3), both hormone levels remained normal until term. Thus human placental lactogen rather than estriol is a good indicator of intrauterine growth retardation in twin pregnancy. Both human placental lactogen and estriol are useful for the monitoring of the surviving fetus in the case of single intrauterine fetal death.

Adult↗
PubMed1986

The circadian pattern of melatonin and its positive relationship with progesterone in women.

To investigate the possible role of melatonin in the regulation of the human menstrual cycle, the circadian pattern of melatonin was determined in the follicular and luteal phases of 10 normal women. Four-hourly sampling was used to derive a melatonin index which described the total exposure to melatonin for 24 h. This sampling procedure adequately represented the circadian melatonin output and demonstrated that pulses of melatonin secretion, inconsistent with a measured half-life of 47 min, did not exist. A significant increase (P less than 0.001) in the melatonin index was found in the luteal phase compared to that in the follicular phase. To investigate the influence of exogenous progestins on the melatonin pattern, repeated 24-h profiles were measured in 8 women taking the 3-phase contraceptive pill. There was a significant increase (P less than 0.01) in the melatonin index associated with an increase in the dose of progestin. These results are consistent with a positive relationship between melatonin and progesterone and suggest that changes in the circadian pattern of melatonin secretion, rising during the luteal phase with a fall before ovulation, may act as a modulator of cyclicity.

Administration, Intranasal↗
PubMed1985

Determination of infused (13C)progesterone in ovarian arterial blood by selected ion monitoring.

Gas chromatography mass spectrometry (GC/MS) with selected ion monitoring (SIM) is employed to detect and approximate the levels of (13C)progesterone is small blood samples obtained at intervals from ipsilateral and contralateral ovarian arteries and a peripheral vein before, during and after infusion into the utero-ovarian vein (five women during hysterectomy). The internal standard was 16 alpha-methylprogesterone. The method is rapid and allows the time course of the infused hormone to be plotted in spite of large and rapidly fluctuating concentrations of endogenous progesterone. The results show for the first time the local in vivo transfer of a steroid hormone from the uterine vein to the adjacent ovary in humans.

Adult↗
PubMed1985

Desensitization of mouse Leydig cells in vivo: evidence for the depletion of cellular cholesterol.

The study presents a characterization of the refractory state in purified mouse Leydig cells desensitized by a single injection of human chorionic gonadotropin (hCG) in vivo. The treatment of mice with 1 microgram hCG i.p. for 48 h followed by Leydig cell isolation and purification resulted in a decrease in the maxima of hCG-induced cAMP accumulation and testosterone production by approximately 70% and approximately 55%, respectively, when compared to cells of control mice. Despite a 55% reduction in 125I-hCG binding sites, the sensitivity of stimulation was not changed. The refractoriness in testosterone production in vitro was also present when the Leydig cells were stimulated with cholera toxin or dibutyryl cAMP; however, it was not observed when testosterone production was induced by the addition of pregnenolone or 20 alpha- and 22(R)-hydroxycholesterol. Mouse lipoproteins, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) in natural composition, were also able to overcome the steroidogenic block (although not always completely). On the basis of the cholesterol content of the lipoproteins, the two classes were similarly effective. They increased maximal hCG-induced testosterone production not only in desensitized cells, but also in control cells (by 80-100%), whereas their effect on basal testosterone production was negligible. In desensitized cells from hCG-treated mice (2 micrograms i.p., 48 h) cellular unesterified and esterified cholesterol were decreased by 21% and 81%, respectively, when compared to control cells. This loss occurred in the face of unchanged plasma cholesterol levels. In conclusion, our data indicate that the impaired steroidogenesis in mouse Leydig cells desensitized in vivo by a single injection of hCG is the result of a depletion in cellular cholesterol, rather than of an impaired conversion of cholesterol to testosterone.

Animals↗