Hormone replacement therapy in galactosaemic twins with ovarian failure and severe osteoporosis.
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Biomedical subjects
Publications and source records attributed to L Wildt.
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The inhibition of LDL-oxidation by 17-alpha estradiol was assessed in vitro by the determination of the duration of the lag-phase in copper ion-induced oxidation and compared to that of 17-beta estradiol, estriol, and probucol. Addition of 0.2, 0.4, and 1 micromol/l of the test substances prolonged the lag-phase of LDL-oxidation 1.3-(+/-0.09 SD), 1.7-(+/-0.14 SD), and 2.7-(+/-0.25 SD) fold for 17-alpha estradiol; 1.4-(+/-0.14 SD), 1.8-(+/-0.1 SD), and 2.6-(+/-0.16 SD) fold for 17-beta estradiol; 1.1-(+/-0.07 SD), 1.4-(+/-0.11 SD), and 1.6-(+/-0.11 SD) fold for estriol as well as 1.4-(+/-0.14 SD), 1.6-(+/-0.1 SD), and 3.0-(+/-0.21) fold for probucol, thus proving that 17-alpha estradiol is as effective as 17-beta estradiol or similar to probucol and more effective than estriol (n = 6 in all cases). These data demonstrate that 17-alpha estradiol is able to delay LDL-oxidation, hence providing a basis for clinical examination of the protective effects of 17-alpha estradiol against atherosclerosis in patients where hormonal effects of 17-beta estradiol are undesirable.
Several studies suggest that leptin modulates hypothalamic-pituitary-gonadal axis functions. Leptin may stimulate release of gonadotrophin releasing hormone (GnRH) from the hypothalamus and of gonadotrophins from the pituitary. A synchronicity of luteinizing hormone (LH) and leptin pulses has been described in healthy women and in patients with polycystic ovarian syndrome, suggesting that leptin may modulate the episodic secretion of LH. However, it has not been established whether LH regulates the episodic secretion of leptin. To further examine LH-leptin interactions, we studied the episodic fluctuations of circulating LH and leptin in two patients with Kallmann's syndrome (KS) before and on day 7 of pulsatile GnRH administration, and compared these with those observed in the early follicular phase of 10 regularly menstruating women divided into two control groups according to the body mass index of each patient. To assess episodic hormone secretion, blood samples were collected at 10 min intervals for 6 h, before and on day 7 of GnRH administration in KS patients, and during days 3-7 of the follicular phase in normally cycling women. LH and leptin concentrations were measured in all samples. For pulse analysis, the cluster algorithm was used. Before treatment, an apulsatile pattern with no endogenous LH pulsations was observed in both KS patients. However, leptin pulses were assessed in both women. During GnRH administration, pulsatile LH activity was achieved in both patients with pulse characteristics similar to those of the respective control group. Serum leptin concentrations and leptin pulsatile patterns were not modified. These results suggest that circulating leptin is probably not modulated by pulsatile GnRH-LH secretion.
Animal and human studies suggest that leptin modulates hypothalamic-pituitary-gonadal axis functions. Leptin may stimulate gonadotrophin-releasing hormone (GnRH) release from the hypothalamus and luteinizing hormone (LH) and follicle stimulating hormone (FSH) secretion from the pituitary. A synchronicity of LH and leptin pulses has been described in healthy women, suggesting that leptin probably also regulates the episodic secretion of LH. In some pathological conditions, such as polycystic ovarian syndrome (PCOS), LH-leptin interactions are not known. The aim of the present investigation was to assess the episodic fluctuations of circulating LH and leptin in PCOS patients compared to regularly menstruating women. Six PCOS patients and six normal cycling (NC) women of similar age and body mass index (BMI) were studied. To assess episodic hormone secretion, blood samples were collected at 10-min intervals for 6 h. LH and leptin concentrations were measured in all samples. For pulse analysis the cluster algorithm was used. To detect an interaction between LH and leptin pulses, an analysis of copulsatility was employed. LH concentrations were significantly higher in the PCOS group in comparison to NC women, however serum leptin concentrations and leptin pulse characteristics for PCOS patients did not differ from NC women. A strong synchronicity between LH and leptin pulses was observed in NC women; 11 coincident leptin pulses were counted with a phase shift of 0 min (P = 0.027), 18 pulses with a phase shift of -1 (P = 0.025) and 24 pulses with a phase shift of -2 (P = 0.028). PCOS patients also exhibited a synchronicity between LH and leptin pulses but weaker (only 20 of 39 pulses) and with a phase shift greater than in normal women, leptin pulses preceding LH pulses by 20 min (P = 0.0163). These results demonstrate that circulating leptin and LH are synchronized in normal women and patients with PCOS. The real significance of the apparent copulsatility between LH and leptin must be elucidated, as well as the mechanisms that account for the ultradian leptin release.
In previous papers we provided evidence for a glucocorticoid (GC) responsive site in a highly purified rat liver plasma membrane (PM) fraction, which has proved to be osmotically active, 'right side-out' vesicles, free of CBG, glucocorticoid receptors (GR) and ATP (J. Steroid Biochem. Molec. Biol. 42 (1992) 737-756 and 757-771). This site, now called 'GC importer', mediates active transmembrane transport of corticosterone (B). Pronounced specificity, including stereo- and enantiomeric specificity, of ligand-GC importer interaction was demonstrated by competition assays using 54 different steroidal hormones and molecules. Important structural prerequisites for ligands with high specificity for the GC importer are plane C21-steroid hormones with 1-ene and/or 4-ene or 5alpha-reduced configuration, and/or OH-group(s) at C11beta>C17alpha>C21. Unexpectedly, other preferred ligands are C17alpha-ethynyl steroids like estrogens with an OH- or OCH3-group at C3 (EE2, mestranol) as well as progestins with C3-OH and 4-ene configuration (ethynodiol). C21-steroids with 11alpha-OH, 11-keto, 16alpha-CH3, 16beta-CH3, 16alpha-OH or 5beta-reduced configuration are low specificity ligands. The importer even displays different specificity for enantiomers (levonorgestrel>L-norgestrel). Altogether, the GC importer preferentially recognizes active GC and natural progestins which act as GC-antagonist (e.g. prednisolone>11beta-cortisol = B > or = progestins). Synthetic GC-agonists (e.g. dexamethasone, betamethasone, triamcinolone), most synthetic progestins, biologically inactive GC (e.g. 11alpha-cortisol, prednisone, cortisone, 11-dehydro-B), mineralocorticoids (aldosterone), natural estrogens (e.g. E1, E2, E3), DES and vitamin D3 derivatives do not interact with the GC importer. Osmotic shrinkage experiments revealed that interaction of high as well as low specificity ligands with the GC importer comprises reversible binding and transport through the PM. The ligand specificity profile of the GC importer and the GR exhibit pronounced differences, suggesting that both GC recognizing sites are different proteins. Performing immunoblotting, using specific mono- and polyclonal antibodies directed against the intracellular rat GR, of the PM pretreated with the membrane protein solubilizing detergent CHAPSO, we found that specific steroid binding to the PM site is not due to contamination with GR. Colchicine, daunorubicine, quinine, reserpine, verapamil and vinblastine, representatives of lipophilic xenobiotics which are known to be transported out of cells by the glycoprotein P170, did not compete with B for uptake into PM-vesicles, indicating that the GC importer is not a member of the ABC/mdr superfamily. The GC importer seems to be an additional link in the chain of steroid signal transduction and may be functionally involved in the action of natural GC-agonists and GC-antagonists.
A total of 12 women (24.2 +/- 1.6 years old, BMI 36.7 +/- 1.5 Kg/m2) with hyperandrogenism (HA) and with normal glucose tolerance test were studied to evaluate the involvement of endogenous opioids in the pathophysiology of insulin secretion and insulin sensitivity in HA by administering naltrexone, an oral opioid receptor antagonist. Six patients received naltrexone orally (75 mg daily) and another six received placebo for 12 weeks (double-blind study). Before and after therapy a frequently sampled intravenous glucose tolerance test (FSIVGTT) was performed. The insulin sensitivity index (SI) was determined by Bergman's program. SHBG, DHEAS, testosterone, free androgen index (FAI) and plasma concentrations of IGF-I and IGFBP-1 were determined in 3 basal samples, before and after therapy. Treatment with naltrexone in hyperandrogenic patients resulted in a decrease in fasting insulin concentrations of 40% and C-peptide concentrations of 50% (p < 0.05). Insulin and C-peptide from the FSIVGTT displayed a similar pattern with a fall in the area under the curve under naltrexone treatment of 34% for insulin and 35% for C-peptide. Insulin sensitivity did not change under naltrexone (1.26 +/- 0.19 vs 1.32 +/- 0.32 10(-4) x min(-1)/(uU/ml)) or placebo (0.95 +/- 0.19 vs 1.12 +/- 0.28 10(-4) x min(-1)/(uU/ml)) administration. However, glucose effectiveness increased significantly with naltrexone (2.231 +/- 0.002 vs 3.354 +/- 0.006 x 10(-2) min(-1)). Glucose (fasting and area under the curve) was not modified significantly after naltrexone administration. Baseline hormone levels were similar in the two groups, and they did not change after long-term treatment with naltrexone or placebo. In conclusion, these results support the hypothesis of elevated opioid tonus and increased insulin secretion as a possible mechanism of hyperinsulinism in a group of hyperandrogenic women of ovarian origin. This alteration could act as an additional factor in the pathogenesis of insulin resistance found in an important proportion of these patients.
The hCG/LH receptor belongs to the G-protein coupled receptor family. The gene for the receptor has been localised to chromosome 2p21. In addition to corpus luteum and testis as the classical target tissues for hCG and LH, hCG/LH receptors have been described in a variety of non-gonadal human tissues (e.g. endometrium, myometrium, fallopian tube, placenta, amnion, chorion, prostate, CNS, adrenal gland). Besides its modulation of endocrine functions, the hCG/LH receptor does probably transmit growth-factor like activities of hCG and LH in many of these tissues. Moreover, activating as well as inactivating mutations of the hCG/LH receptor gene have been described. These mutations are localised mainly within the transmembrane region of the receptor gene (exon 11) and are responsible for characteristic diseases such as familiar, male-limited precocious puberty as well as hypogonadism of both sexes. This review deals with the molecular biology of the hCG/LH receptor, its distribution within the human body, its functions as well as with the relevance of mutations. Finally, the therapeutic use of hCG in the treatment of AIDS-related Kaposis' sarcoma is discussed.
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The physiological and the pathophysiological basis of unvariant pulsatile administration of gonadotrophin-releasing hormone (GnRH) as well as the clinical results are reviewed. Pulsatile administration of GnRH not only proved to be a very effective treatment mode but also became an important tool for research in the central control of pituitary and ovarian function under normal and disease conditions.
17 alpha-Hydroxylase Deficiency (17 alpha-OHDS) is a rare defect of steroid biosynthesis, characterized by the inability to synthesize cortisol, androgens or estrogens, by the complete absence of follicular maturation, hypergonadotropic hypogonadism, primary amenorrhea and hypertension. Since the ovaries of such patients contain numerous primordial follicles, we hypothesized that the absence of spontaneous follicular maturation could be due to a lack of aromatizable substrate. To provide this substrate, testosterone was administered either by intra-ovarian injection or by vaginal administration. Ovarian stimulation was performed with human urinary gonadotropins. Follicular maturation and ovulation could be induced by this treatment, as determined from ultrasonography, the analysis of LH, estradiol and progesterone serum levels and the aspiration of oocytes from the mature follicles. Fertilization of these oocytes in vitro, however, did not succeed. We conclude that follicular maturation can be induced in 17 alpha-OHDS by gonadotropins when testosterone is provided as an aromatizable substrate and that estrogens are a necessary component of follicular maturation.
Recurrence in Four Consecutive Pregnancies in a Patient: We report on the recurrence of HELLP-syndrome in four consecutive pregnancies in a patient. The observation of recurrence of this rare disorder (0.2-0.8% of all pregnancies) in an otherwise healthy patient points to an immunological or genetic predisposition for the development of HELLP-syndrome. At the moment there is no possibility to identify these patients with a high recurrence risk for HELLP-syndrome before the onset of pregnancy.
Vaginal ultrasonography of uterine peristalsis during the follicular phase of the menstrual cycle demonstrates an increasing frequency and intensity of subendometrial and myometrial peristaltic waves as the follicular phase progresses. During this time the numbers of contraction waves with a fundo-cervical direction decrease considerably in favour of waves of contraction with a cervico-fundal direction. There is evidence that rapid sperm transport through the female genital tract is passive and is provided by these uterine contractions. Using hysterosalpingoscintigraphy, rapid sperm transport was studied by placing technetium-labelled albumin macrospheres of sperm size at the external os of the uterine cervix and following their path through the female genital tract. Ascension of the macrospheres occurred immediately following deposition at the external os of the cervix. As early as 1 min thereafter, the macrospheres had reached the intramural and isthmical part of the tube. Quantitatively, the extent of ascension increased with progression of the follicular phase. While only a few macrospheres entered the uterine cavity and even fewer the tubes during the early follicular phase, the proportion of macrospheres that entered the uterine cavity increased dramatically during the mid-follicular phase despite continuing limited entry into the tube. During the late follicular phase there was considerable ascension of the macrospheres which was directed preferentially into the tube ipsilateral to the dominant follicle. These data indicate that rapid transport of the spermatozoa through the female genital tract is under the endocrine control of the dominant follicle, ensuring the preferential accumulation of spermatozoa at the site of fertilization.
Women suffering from infertility in association with mostly mild endometriosis were subjected to vaginal sonography of uterine peristalsis during the menstrual period, the early, mid- and late follicular phases, and the mid-luteal phase of the menstrual cycle. The data obtained were compared with those of healthy controls. Women with endometriosis displayed a marked uterine hyperperistalsis that differed significantly from the peristalsis of the controls during the early and mid-follicular and mid-luteal phases. During the late follicular phase of the cycle, uterine peristalsis in women with endometriosis became dysperistaltic, arrhythmic and convulsive in character, while in controls peristalsis continued to show long and regular cervico-fundal contractions. Hysterosalpingoscintigraphy during the early, mid- and late follicular phases revealed that hyperperistalsis in the early and mid-follicular phases of patients with endometriosis resulted in a dramatic increase in the transport of inert particles from the vaginal depot, through the uterus into the tubes and also into the peritoneal cavity. During the late follicular phase of the cycle, the dysperistalsis observed in women with endometriosis resulted in a dramatic reduction of uterine transport capacity in comparison with the healthy controls. We consider uterine hyperperistalsis to be the mechanical cause of endometriosis rather than retrograde menstruation. Dysperistalsis in the late follicular phase of patients with endometriosis may compromise rapid sperm transport. Uterine hyperperistalsis and dysperistalsis are considered to be responsible for both reduced fertility and the development of endometriosis.
OBJECTIVE: To assess stress hormone response in traumatised patients studied at the site of injury and on their way to hospital. METHODS: The study was prospective. Blood samples were taken from 77 patients immediately after the arrival of the emergency physician at the site of the accident (t1) and shortly before patients' admission to hospital (t2). Plasma concentrations of beta endorphin, cortisol, adrenocorticotrophic hormone (ACTH), prolactin, and growth hormone were measured. RESULTS: Trauma in out-of-hospital patients resulted in remarkably increased concentration of growth hormone within minutes. ACTH, cortisol, and prolactin were only moderately increased. No significant correlations were found between hormone levels and blood pressure or heart rate. The plasma ACTH concentration was significantly lower before admission to hospital than immediately after the accident. Plasma cortisol, prolactin, and growth hormone concentrations were not significantly different between the two points of observation. In samples taken immediately after the accident (t1), there was a positive correlation between both beta endorphin and prolactin and the injury severity score, whereas cortisol levels were negatively correlated with injury severity score, suggesting impaired cortisol release from the adrenal cortex after severe injury. At t1 ACTH was correlated with cortisol and beta endorphin. Patients with head injuries had hormone concentrations similar to those without head injuries but with a similar injury severity score from injuries in other parts of the body. CONCLUSIONS: Lower cortisol concentrations in the very severely injured might be due to failure of the adrenal cortex to respond normally to ACTH stimulation. Growth hormone seems to play a major role in the response to trauma, reflecting an immediate stress response.
A simple system for the continuos withdrawal of blood and the serial collection of blood samples in human subjects and experimental animals is described. It consists of heparin-coated tubing, a connector attached to an indwelling cannula that allows flushing of the i.v. catheter, a peristaltic pump and a fraction collector and an alarm system which is activated when blood flow through the system is interrupted. It can be assembled from parts available in every laboratory or hospital.
The authors report on a patient who was pretreated with a depot GnRH-analog previous to exogenous gonadotropin stimulation before in-vitro fertilisation (IVF). The patient had an undiagnosed ectopic pregnancy. Folliculogenesis and the hormone profile were normal. In patients with patent tubes, contraception (non-hormonal) in the cycle previous to IVF should be performed.
The diagnosis of a partial hydatid mole presents a difficult situation for both physician and parents. On the one hand there may be a normal pregnancy whereas on the other hand the mother may be threatened by numerous complications caused by the hydatid mole if the pregnancy is continued. We report on a pregnancy in the 18th week during which a partial hydatid mole was discovered where we considered it justified to advise the parents, after a thorough consultation, to continue with the pregnancy. Ultrasound examination had excluded infaust malformations whereas cytogenetically there was no triploidy of the fetus. Moreover it was possible to closely monitor the course of pregnancy to discover any possible complications well in time. Under these conditions continuation of pregnancy until birth is possible in about 60% of the cases without enhanced risk to the mother, as is evident from the data in the literature. In the case under report, however, there was a life-threatening uterine haemorrhage with placenta previa in the 22nd week of pregnancy resulting in mandatory premature termination of pregnancy. Repeated treatment with cytostatics was subsequently required due to persistence of the mole, since even hysterectomy could not achieve complete remission of the disease.
In this study the role of gonadotropins for the induction of ovarian tumors in rats was examined. The rats were castrated and one ovary was transplanted under the splenic capsule. Rats remained untreated or received a GnRH analog for gonadotropin suppression either immediately, 90 or 180 days after castration. Under these conditions the untreated rats developed ovarian tumors while the treated rats only developed tumors when the stimulation of gonadotropins lasted for more than 90 days. The first appearing tumors were theca cell tumors while during the further course of the experiment the granulosa cell compartment increased; however, no histological signs of malignancy could be detected in these tumors. GnRH analogs could block the induction of granulosa cell tumors when administered 150 days after transplantation. After a period of 210-240 days the tumors grew independently of elevated LH and FSH levels. The causes of this growth autonomy need to be studied further.