Comment on electrodipping force acting on solid particles at a fluid interface.
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Comment↗
Biomedical subjects
M Oettel
Publications and source records attributed to M Oettel.
High-dose pilot study with the novel progestogen dienogestin patients with endometriosis.
High-dose dienogest (20 mg/day) was used for the treatment of endometriosis in women aged 18-52 years after laparoscopic and histological diagnosis of endometriosis and staging according to the revised American Fertility Society criteria. Treatment efficacy was analyzed objectively by second-look laparoscopy, and serum hormone measurements and evaluation of endometriosis-related symptoms were performed done and side-effects recorded. Compared with other high-dose progestin therapies, treatment with dienogest was shown to be effective even in stage IV endometriosis. The side-effect profile of the high-dose dienogest treatment appears to be highly favorable compared with other treatments. Neither the menopausal symptoms caused by therapy with gonadotropin-releasing hormone agonists nor the adverse androgen-related effects induced by danazol were observed. Therefore, long-term high-dose dienogest therapy can be recommended particularly for women with progressive endometriosis.
Adult↗
Dehydroepiandrosterone treatment in the aging male--what should the urologist know?
OBJECTIVE: Dehydroepiandrosterone (DHEA) has attracted considerable attention as a means against the decrements of aging. This review will summarize clinical studies evaluating DHEA as a treatment option for age-related conditions and diseases. METHODS: Literature search of PubMed documented publications and abstracts from meetings. RESULTS: The collected data indicate that DHEA supplementation to counteract its gradual decrease over age is beneficiary. Positive effects on the cardiovascular system, body composition, BMD, the skin, the CNS, and the immune system have been reported. Improvement of sexual function by DHEA has been demonstrated. CONCLUSION: Although long-term clinical trials (applying the standards of evidence-based methods) are not available at present, the consistency of the data and the extensive practical experience may justify the use of DHEA in aging men given the rules of classical endocrinology are thoroughly followed including diagnosis based on clinical picture and biochemical evidence, compliance to periodic evaluations, and individual dose adjustment to maintain serum concentrations in the physiological range of young males. Being one among other important hormonal factors, DHEA can delay and correct age-related disorders only to a certain degree.
Aging↗
Effective capillary interaction of spherical particles at fluid interfaces.
We present a detailed analysis of the effective force between two smooth spherical colloids floating at a fluid interface due to deformations of the interface in an inhomogeneous pressure field. The results hold in general and are applicable independently of the source of the deformation provided the capillary deformations are small so that a superposition approximation for the deformations is valid. We conclude that an effective long-ranged attraction is possible if the net force on the system does not vanish. Otherwise, the interaction is short ranged and cannot be computed reliably based on the superposition approximation. As an application, we consider the case of like-charged, smooth nanoparticles and electrostatically induced capillary deformation. The resulting long-ranged capillary attraction can be easily tuned by a relatively small external electrostatic field, but it cannot explain recent experimental observations of attraction if these experimental systems were indeed isolated.
Journal Article↗
Solvent mediated interactions close to fluid-fluid phase separation: microscopic treatment of bridging in a soft-core fluid.
Using density functional theory we calculate the density profiles of a binary solvent adsorbed around a pair of big solute particles. All species interact via repulsive Gaussian potentials. The solvent exhibits fluid-fluid phase separation, and for thermodynamic states near to coexistence the big particles can be surrounded by a thick adsorbed "wetting" film of the coexisting solvent phase. On reducing the separation between the two big particles we find there can be a "bridging" transition as the wetting films join to form a fluid bridge. The effective (solvent mediated) potential between the two big particles becomes long ranged and strongly attractive in the bridged configuration. Within our mean-field treatment the bridging transition results in a discontinuity in the solvent mediated force. We demonstrate that accounting for the phenomenon of bridging requires the presence of a nonzero bridge function in the correlations between the solute particles when our model fluid is described within a full mixture theory based upon the Ornstein-Zernike equations.
Journal Article↗
Depletion force between two large spheres suspended in a bath of small spheres: onset of the Derjaguin limit.
We analyze the depletion interaction between two hard colloids in a hard-sphere solvent and pay special attention to the limit of large size ratio between colloids and solvent particles which is governed by the well-known Derjaguin approximation. For separations between the colloids of less than the diameter of the solvent particles (defining the depletion region), the solvent structure between the colloids can be analyzed in terms of an effective two-dimensional gas. Thereby we find that the Derjaguin limit is approached more slowly than previously thought. This analysis is in good agreement with simulation data which are available for a moderate size ratio of 10. Small discrepancies in results from density functional theory (DFT) at this size ratio become amplified for larger size ratios. Therefore we have improved upon previous DFT techniques by imposing test-particle consistency which connects DFT to integral equations. However, the improved results show no convergence towards the Derjaguin limit and thus we conclude that this implementation of DFT together with previous ones which rely on test-particle insertion become unreliable in predicting the force in the depletion region for size ratios larger than 10.
Journal Article↗
The effects of estrogens on learning in rats with chronic brain cholinergic deficiency in a Morris water test. Identification of the "passive swimming" component.
Chronic decreases in brain cholinergic functions due to intraventricular administration of the neurotoxin AF64A were accompanied by increases in the latent period of locating an invisible platform during training of rats in a Morris water test, as compared with control sham-operated animals. Recordings of the animals' movement trajectories using a video camera along with an original computer program (Behavioral Vision) showed that administration of 17beta-estradiol and its synthetic analog J-861 (0.2 mg/kg p.o. daily for seven days before and 10 days after single intraventricular injections of AF64A) improved learning. The directivity of platform search trajectories was assessed quantitatively using a new parameter--trajectory straightness. Introduction of the "passive swimming" parameter allowed periods of immobility in water to be identified within the total latent period in animals after administration of AF64A; 17beta-estradiol but not J-861 "eliminated" these periods. The new parameters (especially trajectory straightness) allowed the ability to learn to be discriminated from decreases in mobility, including mobility losses due to study agents, in the Morris water test.
Adrenal Glands↗
Progesterone: the forgotten hormone in men?
'Classical' genomic progesterone receptors appear relatively late in phylogenesis, i.e. it is only in birds and mammals that they are detectable. In the different species, they mediate manifold effects regarding the differentiation of target organ functions, mainly in the reproductive system. Surprisingly, we know little about the physiology, endocrinology, and pharmacology of progesterone and progestins in male gender or men respectively, despite the fact that, as to progesterone secretion and serum progesterone levels, there are no great quantitative differences between men and women (at least outside the luteal phase). In a prospective cohort study of 1026 men with and without cardiovascular disease, we were not able to demonstrate any age-dependent change in serum progesterone concentrations. Progesterone influences spermiogenesis, sperm capacitation/acrosome reaction and testosterone biosynthesis in the Leydig cells. Other progesterone effects in men include those on the central nervous system (CNS) (mainly mediated by 5alpha-reduced progesterone metabolites as so-called neurosteroids), including blocking of gonadotropin secretion, sleep improvement, and effects on tumors in the CNS (meningioma, fibroma), as well as effects on the immune system, cardiovascular system, kidney function, adipose tissue, behavior, and respiratory system. A progestin may stimulate weight gain and appetite in men as well as in women. The detection of progesterone receptor isoforms would have a highly diagnostic value in prostate pathology (benign prostatic hypertrophy and prostate cancer). The modulation of progesterone effects on typical male targets is connected with a great pharmacodynamic variability. The reason for this is that, in men, some important effects of progesterone are mediated non-genomically through different molecular biological modes of action. Therefore, the precise therapeutic manipulation of progesterone actions in the male requires completely new endocrine-pharmacological approaches.
Animals↗
Intramuscular testosterone undecanoate: pharmacokinetic aspects of a novel testosterone formulation during long-term treatment of men with hypogonadism.
In an open-label, randomized, prospective trial, we investigated pharmacokinetics and several efficacy and safety parameters of a novel, long-acting testosterone (T) undecanoate (TU) formulation in 40 hypogonadal men (serum testosterone concentrations < 5 nmol/liter). For the first 30 wk (comparative study), the patients were randomly assigned to receive either 10 x 250 mg T enanthate (TE) im every 3 wk (n = 20) or 3 x 1000 mg TU im every 6 wk (loading dose) followed by 1 x 1000 mg after an additional 9 wk (n = 20). In a follow-up study, observation continued in those patients who completed the comparative part and opted for TU treatment (8 x 1000 mg TU every 12 wk in former TU patients and 2 x 1000 mg TU every 8 wk plus 6 x 1000 mg every 12 wk in former TE patients) for an additional 20-21 months. Here we report only the pharmacokinetic aspects of the new TU formulation for the first approximately 2.5 yr of treatment. At baseline, serum T concentrations did not significantly differ between the two study groups. In the TE group, mean trough levels of serum T were always less than 10 nmol/liter before the next injection, whereas in the TU group, mean trough levels of serum T were 14.1 +/- 4.5 nmol/liter after the first two doses (6-wk intervals) and 16.3 +/- 5.7 nmol/liter after the 9-wk interval at wk 30. The mean serum levels of dihydrotestosterone and estradiol also increased in parallel to the serum T pattern and remained within the normal range. In the follow-up study, the former TU patients (n = 20) received eight TU injections at 12-wk intervals, and the TE patients (n = 16) switched to TU and initially received two TU injections at 8-wk intervals (loading) and continued with six TU injections at 12-wk intervals (maintenance). This regimen resulted in stable mean serum trough levels of T (ranging from 14.9 +/- 5.2 to 16.5 +/- 8.0 nmol/liter) and estradiol (ranging from 98.5 +/- 45.2 to 80.4 +/- 14.4 pmol/liter). The present study has shown that 1000 mg TU injected into male patients with hypogonadism at 12-wk intervals is well tolerated and leads to T levels within normal ranges, using four instead of 17 or more TE injections per year. An initial loading dose of either 3 x 1000 mg TU every 6 wk at the beginning of hormone substitution or 2 x 1000 mg TU every 8 wk after switching from the short-acting TE to TU were found to be a adequate dosing regimens for starting of treatment with the long-acting TU preparation.
Adolescent↗
Testosterone metabolism, dose-response relationships and receptor polymorphisms: selected pharmacological/toxicological considerations on benefits versus risks of testosterone therapy in men.
In this review selected toxicological problems related to testosterone therapy in hypogonadal men are discussed. Applying "classical" pharmacological/toxicological findings (e.g. animal studies on short- and long-term toxicity) to clinical situations is not very helpful. Molecular biological knowledge and especially evaluation of epidemiological studies, as well as intervention studies, on testosterone therapy in hypogonadal men are more useful. Potential risks include overdosage for lifestyle reasons, e.g. excessive muscle building and reduction of visceral obesity, when erythrocytosis occurs concomitantly. Modern galenic formulations of testosterone administration (e.g. transdermal gel, suitable testosterone esters for intramuscular application and newer oral preparations) avoid supraphysiological serum concentrations, therefore significantly reducing the toxicological risk. A hypothetical model of the toxicological risks of testosterone therapy is given that is based on the influence of testosterone metabolism (aromatization vs. reduction) of the respective parameter/target chosen. Finally, the great influence of polymorphisms of the androgen receptor on the assessment of toxicological risk and on the individualization of androgen therapy is shown. Already existing national, continental and international guidelines or recommendations for the testosterone therapy should be harmonized.
Dose-Response Relationship, Drug↗
Estradiol, testosterone, dehydroepiandrosterone and androstenedione: novel derivatives and enantiomers. Interactions with rat liver microsomal cytochrome P450 and antioxidant/radical scavenger activities in vitro.
Interactions of 27 steroids, among them 17 derivatives such as ethers, sulfates and amidosulfonates derived from 17 beta- and 17 alpha-estradiol, from testosterone and alpha- and beta-dihydrotesosterone and from dehydroepiandrosterone with rat liver microsomal cytochromes P450 (P450) were investigated in vitro by assessing binding to P450 and effects on P450 mediated monooxygenase functions as measured by different model reactions: ethoxyresorufin O-deethylation (EROD), ethoxycoumarin O-deethylation (ECOD) and ethylmorphine N-demethylation (EMND). With the exception of 17 alpha-estradiol-3-dimethylamidosulfonate, estrone, its -3-methylether and -3-amidosulfonate and testosterone, all other steroids displayed type I or reverse type I binding to P450. All steroids inhibited EROD activity in micromolar concentrations. An additional strong inhibition of ECOD and EMND activities was only demonstrated for the androgens and progestins. Estriol, estrone and mestranol displayed less inhibitory actions on the model reactions than estradiol. No major differences in comparison to the parent compounds were noted with the other derivatives. The only exceptions were 17 beta-(8,9-dehydro-14 alpha,15 alpha-methylene)estradiol, which displayed stronger effects than estradiol, and dehydroepiandrosterone-3-sulfate, which was less effective than dehydroepiandrosterone. Possible antioxidant properties of the steroids were examined by the stimulated lipid peroxidation (LPO), H2O2 production, and lucigenin (LC) and luminol (LM) amplified chemiluminescence (CL) using rat liver microsomes. Additionally, the influence on rat whole blood chemiluminescence (WB-CL) was assessed. All the estrogens, but not their methylethers and amidosulfonates inhibited LPO in micromolar concentrations. The effects on the other oxidase model reactions or on WB-CL were less distinct. Only ethinylestradiol and 17 beta-(8,9-dehydro-14 alpha,15 alpha-methylene)estradiol displayed a strong inhibitory action on all model reactions. With the exception of dehydroepiandrosterone-3-sulfate, which in general had only weak effects, the androgen and progestin derivatives, in contrast, strongly decreased H2O2 formation and LM- and LC-CL, but were mostly ineffective on LPO and WB-CL.
7-Alkoxycoumarin O-Dealkylase↗
Is there a role for estrogens in the maintenance of men's health?
This paper gives an overview of our own studies and the literature on the biosynthesis and metabolism of estrogens in elderly men, the estrogen action in the male, and the clinical usefulness of estrogen therapy, including the phytoestrogens. Finally, the paper includes a short review of our knowledge of xenoestrogens and men's sexual health. A strong estrogen-deficient status is seen in male patients with mutations of the estrogen receptors or in cases of deviations of the aromatase gene. On the other hand, there are no clear age-dependent changes in estrogen secretion. But, in men with disorders of glucose metabolism and also of increased body mass index, the serum estrogen concentrations are significantly elevated. There are also strong positive correlations between serum estrogen levels and bone density, including prevalence of fractures and mood in men. New fields of interest are natural fatty esters of endogenous estrogens, e.g. lipoprotein-associated estrogens, and the role and clinical significance of tissue-specific, local estrogen biosynthesis (e.g. different promoters of the aromatase gene). Exogenous estrogen treatment is focused today on patients with normal testosterone and low levels of circulating estrogens documented on several occasions and with clinical symptoms of hormone deficiency; male-to-female transsexuals; and selected patients with prostate cancer. Some clinical studies show the benefits of estrogen treatment on some cardiovascular parameters and for treating selected signs of mental stress. An indirect estrogen replacement can occur if dehydroepiandrosterone is given orally to men. The clinical usefulness of dissociated estrogens, including non-feminizing estrogens and selective estrogen receptor modulators, is still an open question. The beneficial action of phytoestrogens in lowering the clinical symptoms of benign prostatic hyperplasia is well documented. Finally, the question about the definitive influence of so-called endocrine disruptors (xenoestrogens) on sexual functions in men is also discussed.
Aged↗
Scavenging and antioxidant effects of estrogen derivatives in cholesterol-fed rabbits.
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Animals↗
Double-blind, placebo-controlled psychometric studies on the effects of a combined estrogen-progestin regimen versus estrogen alone on performance, mood and personality of menopausal syndrome patients.
The influence of a combined estrogen-progestin regimen (Climodien) on noopsyche, thymopsyche, personality and psychophysiological measures of menopausal syndrome patients was investigated in a double-blind, placebo-controlled, comparative, randomized 3-arm trial phase (Climodien 2/3 = estradiol valerate (CAS 979-32-8) 2 mg + the progestin dienogest (CAS 65928-58-7) 3 mg = regimen A, estradiol valerate 2 mg = regimen EV, and placebo = regimen P) followed by an open-label phase in which all patients received Climodien 2/2 (estradiol valerate 2 mg + dienogest 2 mg) = regimen A*. 49 women (16, 17, 16 valid patients per arm) aged between 46 and 67 years (mean 58, 58, 56 years, respectively) with the diagnoses of insomnia (G 47.0) related to postmenopausal syndrome (N 95.1) were included in the analysis of the double-blind phase. Both the double-blind and the open-label phase lasted 2 months. Noopsychic investigations demonstrated an improvement in associative verbal memory after 2 months of regimen A, which was significant as compared with both baseline and placebo. Regarding visual memory, regimen A* induced an improvement, which was significantly different from the decline in correct reproductions in the Benton Test observed under estradiol. Errors in the Benton Test decreased significantly after regimen A* as compared with regimen EV. These findings suggest that hormone replacement therapy with estradiol, and even more in combination with dienogest, improves verbal and visual memory, which is in line with the improvement in information processing speed and capacity objectified by event-related potentials (ERP). Thymopsychic investigations demonstrated a significant improvement in somatic complaints and trait anxiety after both regimen A and regimen EV as compared with baseline. State anxiety decreased significantly under regimen A* as compared with EV. The Freiburger Personality Inventory showed an improvement in aggressivity after regimen A* as compared with the preceding placebo as well as an improvement in striving after dominancy after both regimen A and regimen EV as compared with pre-treatment, but also after regimen A* as compared with regimen EV. Extraversion increased after 2 months of regimen A as compared to regimen P. Psychophysiological findings including pupillary and skin conductance variables were not significant.
Affect↗
The effects of postmenopausal hormone replacement therapy and oral contraceptives on the endogenous estradiol metabolism.
The estradiol metabolism may be of clinical relevance in the pathophysiology of various diseases; the increase in D-ring metabolites over A-ring metabolites in breast cancer patients is of special interest. Since estrogen therapy has been blamed for increasing the risk of breast cancer, the effects of hormonal replacement therapy (HRT) and oral contraception were investigated on the ratio of the main D-ring metabolite, 16alpha-hydroxyestrone (16-OHE1), to the main A-ring metabolite, 2-hydroxyestrone (2-OHE1). In our study, hormone replacement therapy (HRT) in postmenopausal women consisted of administration of estradiol valerate either with or without addition of the progestin dienogest. In the second part of the study, women of reproductive age received ethinylestradiol plus dienogest or ethinylestradiol plus norethisterone acetate as oral contraceptives (OC). 2-OHE1 and 16-OHE1 were measured by enzyme immunoassay in 8 h night-urine collected before and after 3 months of hormone administration. With HRT, that is, estradiol valerate or estradiol valerate plus dienogest, the ratios before treatment were 0.47 and 0.60; after 3 months, they were 0.54 and 0.52, respectively. There were no significant differences. With oral contraception, that is, ethinylestradiol plus dienogest or norethisterone acetate, the ratios before administration were 0.62 and 0.68, vs. 0.31 and 0.54 after 3 months, respectively. The ratio after ethinylestradiol and dienogest was significantly lower after treatment. HRT and OC in the estrogen-progestin combinations tested did not impose any negative effects on estradiol metabolism--they did not elicit a higher D-ring metabolism, which is considered to increase breast cancer risk.
Adult↗
Estrogen sulfamates: a new approach to oral estrogen therapy.
Sulfamate substitution (-O-SO2-NH2) at carbon atom 3 of the steroid skeleton leads to orally active prodrugs of estrogens with much higher systemic, but lower hepatic, estrogenic activity than their parent steroids. This dissociation is achieved by first passage through the liver in erythrocytes, followed by systemic hydrolysis which releases the 'parent' estrogen. In the rat, orally administered tritiated estradiol sulfamate, unlike estradiol, appears in the circulation at high concentrations. At Cmax, approximately one third of the administered dose forms a depot in the circulation (98% in erythrocytes, 2% in plasma). Significant estradiol, estrone and estrone sulfate concentrations were recorded in plasma during depletion of the red blood cell pool. Estradiol sulfamate (J995) has no estrogen receptor affinity per se or estrogenic activity in vitro ( i.e. without hydrolysis). Its oral uterotropic activity in rats is approximately 100 times greater than that of estradiol, however, its hepatotropic activity is only marginally elevated. These functions include bile secretion, the secretion of angiotensinogen, lipoproteins (total and high-density lipoprotein cholesterol) and insulin-like growth factor I (IGF-I). Orally administred estradiol sulfamate led to systemic estrogenic effects without significant hepatic responses, whereas estradiol and other 'conventional' estrogens exerted parallel systemic and hepatic estrogenic effects. Sulfamate technology represents an approach to the use of natural estrogens for fertility control and hormone replacement therapy in both genders. In this context, reduced effects on hemostatic factors, angiotensinogen, bile and IGF-I secretion seem the most important aspects. In addition, blood concentrations of estrogens are less variable than with conventional estrogens.
Administration, Oral↗
Dehydroepiandrosterone supplementation in healthy men with an age-related decline of dehydroepiandrosterone secretion.
Serum dehydroepiandrosterone declines with age. Whether this represents a harmful deficiency or an age-related adaptation is not known. Dehydroepiandrosterone replacement in adrenal insufficiency, a state of pathological loss of dehydroepiandrosterone production, improves well-being, mood, and sexuality. To determine the effects of dehydroepiandrosterone in healthy men with a physiological, age-related decline in serum dehydroepiandrosterone sulfate, we conducted a double blind cross-over study in 22 healthy male volunteers (age range, 50-69 yr) with endogenous dehydroepiandrosterone sulfate levels below 4.1 micromol/liter (1500 ng/ml) receiving 4 months of dehydroepiandrosterone (50 mg/d) and 4 months of placebo treatment in random order, with a 1-month washout period. Dehydroepiandrosterone treatment increased serum dehydroepiandrosterone and dehydroepiandrosterone sulfate to concentrations usually found in young men. Circulating androgen levels did not change; however, androgen metabolites increased, indicating enhanced peripheral androgen synthesis. At baseline, psychometric assessment revealed normal well-being and sexuality scores. After 4 months of dehydroepiandrosterone, no effect on sexuality was observed, whereas some mood scores improved slightly, but were not significantly different from scores after placebo. Compared with placebo, dehydroepiandrosterone had no effect on serum lipids, bone markers, body composition, or exercise capacity. Thus, in contrast to previous findings in adrenal insufficiency, we found no obvious benefit of 4 months of dehydroepiandrosterone supplementation in healthy men with a physiological decline of dehydroepiandrosterone production.
Affect↗
Antiatherogenic effects of 17 beta-estradiol and 17 alpha-estradiol and its derivative J811 in cholesterol-fed rabbits with thyroid inhibition.
OBJECTIVE: The aim of this study was to investigate the antiatherogenic effects of 17 beta-estradiol and 17 alpha-estradiol and its derivative J811 (estra-1,3,5(10),8-tetraene-3, 17 alpha-diol), having a non-feminizing effect and high antioxidant potential, in male rabbits. EXPERIMENTAL DESIGN: Male White-Russian rabbits weighing 2.1-2.6 kg were fed either a standard or a high-cholesterol (200 mg/kg) diet, with thyroid function-inhibiting thiouracil (20 mg/kg) combined with cholic acid (40 mg/kg) administered daily in sunflower oil for 3 months. During the last month of the study, estrogens were administered by gavage at a dose of 0.02 or 0.1 mg/kg. RESULTS AND CONCLUSIONS: All three estrogens exerted remarkable antiatherosclerotic effects. Decreases in serum and aortic-wall lipid parameters and the index of atherogenicity were dependent on estrogen dose. Morphological evaluation of the aortic wall (height of plaques, size of plaque relative to aortic half-circumference) showed only weak therapeutic effects with all three estrogens. It is an open question whether the treatment period was too short to reverse the above changes. On the other hand, the data clearly suggest that 17 alpha-estradiol and J811 offer new perspectives for the prevention of atherosclerosis in men, which is similar to that found with 17 beta-estradiol in women.
Animals↗