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Comparison of norgestrel- versus cyproterone acetate-containing hormone replacement therapy on lipid-lipoprotein metabolism.

To compare the effects on the lipid profile of estradiol valerate with norgestrel to a regimen of estradiol valerate with cyproterone acetate. Sixty-four healthy women in their perimenopause or early postmenopause, aged between 40-55 years, were randomized to one of the two 21-day sequential regimens: estradiol valerate 2 mg/day for 21 days and combined with either norgestrel 0.5 mg/day or cyproterone acetate 1 mg/day from day 12 to 21, with 7 days of drug-free interval, for 12 cycles. Lipid profiles were followed at baseline, 6 and 12 cycles. Sixty-one subjects completed the study, 30 in the norgestrel group and 31 in the cyproterone group. During 12 cycles of study, serum HDL cholesterol levels decreased significantly in the norgestrel group (p < 0.01) and were unchanged in the cyproterone group. The levels were significantly lower in the norgestrel group than in the cyproterone group (p < 0.05). No differences were found between groups as regards LDL cholesterol and total cholesterol levels. Triglyceride levels decreased significantly in the norgestrel group (p < 0.01), remained unchanged in the cyproterone group and the levels were significantly different between groups (p < 0.01). In conclusion, the study demonstrated that sequential regimen of estradiol valerate with norgestrel produced less favorable HDL cholesterol but more favorable triglyceride levels than the regimen of estradiol valerate with cyproterone acetate.

Adult↗

The role of antiandrogens in hormone replacement therapy.

The most widely used antiandrogens in clinical practice are cyproterone acetate, a derivative of 17-hydroxyprogesterone, and dienogest, a 19-norprogestin. An established sequential preparation for hormone replacement therapy (HRT) consists of 11 days of 2 mg estradiol valerate, 10 days of 2 mg estradiol valerate with 1 mg cyproterone acetate, followed by a 7-day drug-free interval (Climen, Schering AG, Berlin, Germany). Cyproterone acetate is highly progestogenic, has no androgenic properties, and is antiandrogenic above a certain dose. Cyproterone acetate does not counteract the estrogenic effects of estradiol valerate in Climen. This therapy, therefore, has optimal effects on lipid metabolism and coronary heart disease risk, protects the endometrium and reduces menopausal symptoms, preserves bone and reduces osteoporotic fracture risk, and has antiandrogenic effects on the skin and other androgen-sensitive epidermal structures. Dienogest, on the other hand, will soon be introduced in a continuous combined HRT. Dienogest has a 17 alpha-cyanomethyl group instead of the 17 alpha-ethinyl group typical of the common 19-nortestosterone derivatives. It is also referred to as a hybrid progestogen because it has pharmacodynamic properties (e.g. antiandrogenicity) in common with progesterone derivatives. A fixed formulation containing 2 mg estradiol valerate and 2 mg dienogest (Climodien) for continuous combined HRT has been developed. This formulation had excellent effects on vasomotor and neurovegetative symptoms. The bleeding pattern was generally highly satisfactory and similar to that with Kliogest, as were the results of endometrial biopsies after 12 cycles of treatment. Lipid metabolic changes may be interpreted as beneficial. Dienogest had no adverse effects on the vasorelaxant effect of estradiol valerate in postmenopausal women, as shown by markers of vascular function. Neuropsychological studies utilizing evoked potentials showed shortening effects on sleep latency and an improvement in cognitive information processing. Continuous combined HRT with dienogest, therefore, may come to be regarded as the HRT of choice in postmenopausal patients with mood defects. In summary, HRT with antiandrogenic progestogens has its specific indications with respect to preserving metabolic estrogenicity, specific antiandrogenic effects and specific effects on vigilance and mood disorders.

Androgen Antagonists↗

Methylmalonic/beta-hydroxy-n-valeric aciduria due to methylmalonyl-CoA mutase deficiency.

A patient with methylmalonic and beta-hydroxy-n-valeric aciduria, apparently due to deficiency of methylmalonyl-CoA mutase, is described. The excretion of beta-hydroxy-n-valerate did not parallel that of beta-hydroxypropionate and methylmalonate but was observed, together with beta-keto-n-valerate, only during ketosis. beta-Hydroxy-n-valerate excretion thus correlates primarily not with the pool size of propionyl-CoA but with that of acetyl-CoA, and may occur during ketosis in any disorder causing accumulation of propionyl-CoA.

Amino Acid Metabolism, Inborn Errors↗

Estradiol esters can replace 17 beta-estradiol in the stimulation of DNA and esterase synthesis by MCF-7 cells: a possible role for the estrogen-sensitive MCF-7 cell esterase.

In this communication we extend our earlier observations on estrogen-sensitive carboxyl esterases in MCF-7 human breast cancer cells able to hydrolyze esters of estradiol. Using either estradiol acetate or p-nitrophenyl hexanoate as substrates, esterase activity was found to increase 2-3-fold in MCF-7 cells maintained in the presence of 10(-8) M estradiol. Following sucrose density centrifugation, over 85% of total esterase activity was found in the cytoplasmic fraction. No esterase activity was found in spent media from growing cells. By size exclusion chromatography, estradiol acetate esterase activity exhibited a mol. wt of 45-50 kDa. Attempts to demonstrate incorporation of [3H]estradiol into estradiol fatty acid esters by the above MCF-7 cell line (203P) were unsuccessful, although, such incorporation could be demonstrated in two other MCF-7 cell sublines. Incubation of the 203P cells with 10 nM [3H]estradiol in the presence of 0.5 mM radioinert estradiol acetate resulted in the incorporation of 35 +/- 12% of the label into the estradiol acetate in 10 min. In the absence of radioinert estradiol acetate, no incorporation was observed. When MCF-7 cells were incubated with [3H]estradiol in the presence of a large excess of radioinert estradiol valerate, label was found only in estradiol valerate. Similarly, when the incubation was carried out in the presence of a mixture of radioinert estradiol acetate and valerate, label was incorporated into both esters. We conclude that the apparent formation of radiolabeled estradiol esters by MCF-7 cells incubated under the above conditions, results at least in part, from an esterase-catalyzed exchange reaction. Under conditions where no ester hydrolysis could be detected in the absence of cells, valerate and stearate esters of estradiol were found to be as effective as unesterified estradiol in stimulating esterase synthesis and the incorporation of [3H]thymidine into DNA. These results are consistent with a model in which an intracellular esterase in MCF-7 cells can generate estradiol from an exogenous lipoidal steroid and elicit an estrogen response.

Acetates↗

Prednicarbate activity and benefit/risk ratio in relation to other topical glucocorticoids.

BACKGROUND: Nonhalogenated double esters of prednisolone or hydrocortisone applied topically to the skin have a low atrophogenic potential. However, activity and benefit/risk ratio and therefore the superiority over conventional topical glucocorticoids are not well defined. METHODS: The activities of cream preparations with prednicarbate (0.025% to 0.25%), hydrocortisone aceponate, and hydrocortisone buteprate (0.1%) are compared to the effects of betamethasone 17-valerate (0.1%), hydrocortisone (1%), and two drug-free vehicles in 60 healthy volunteers. Test models are the skin blanching assay (occluded and nonoccluded mode), ultraviolet-induced erythema, and an irritant (sodium dodecyl sulfate) dermatitis. The benefit/risk ratio is derived from the activity in the former models and the reduction of skin thickness as determined previously. RESULTS: Prednicarbate activity increases in a dose-dependent manner. Prednicarbate, 0.25%, and the hydrocortisone double esters appear to be equipotent to betamethasone 17-valerate in the skin blanching test and the ultraviolet-erythema test, but superior to hydrocortisone and the vehicles. Prednicarbate and its vehicle, however, do not reverse irritant dermatitis. The benefit/risk ratios of prednicarbate and hydrocortisone aceponate exceed those with betamethasone 17-valerate. CONCLUSIONS: Prednicarbate and hydrocortisone aceponate are intermediate potent glucocorticoids that are superior to betamethasone 17-valerate because of the improved benefit/risk ratio. Patients with severe atopic dermatitis and those who relapse frequently should profit from the treatment with these newer glucocorticoids.

Administration, Topical↗

Effects of corticosteroids on the growth and metabolism of fibroblasts cultured from human skin.

Hydrocortisone, betamethasone 17-valerate, clobetasone butyrate and clobetasol propionate were tested in vitro for effects on the proliferation and metabolism of six strains of fibroblasts from normal human skin. The different cell strains gave similar results: hydrocortisone and betamethasone valerate slightly enhanced growth at all concentrations (0.0001-10 microgram/ml), but high concentrations of clobetasone butyrate and clobetasol propionate significantly reduced proliferation. Secretion of acid mucopolysaccharide was most inhibited by clobetasone butyrate and clobetasol propionate, then by betamethasone valerate, with hydrocortisone having the least effect. Clobetasol propionate and betamethasone valerate at 10 microgram/ml both reduced collagen synthesis by about 50%; other protein synthesis was less affected.

Betamethasone↗

Function of growth factors for rumen microorganisms. I. Nutritional characteristics of Selenomonas ruminantium.

Nutritional characteristics of Selenomonas ruminantium var. lactilytica isolated from a sheep rumen were studied. The organism required for growth the addition of a clarified rumen fluid to a Trypticase-yeast extract medium with either lactate or glucose as an energy source. The requirement for rumen fluid was found to be satisfied by volatile fatty acids in glucose media and by biotin in lactate media. Straight-chain saturated fatty acids with C(3) to C(10) carbon skeleton had been found to be effective. Among them, n-valerate was most effective at the lowest concentration. An abnormal morphology was observed with n-valerate-deficient glucose media. n-Valerate was essential in glucose media, and it was stimulatory in lactate media. Fermentation products from glucose were lactate, propionate, and acetate, and fermentation products from lactate were propionate and acetate. When cells were grown in a glucose medium containing n-valerate-C(14), the label was present in cell fractions. Almost all of the activity was found in lipid materials.

Animals↗

Volatile fatty acid requirements of cellulolytic rumen bacteria.

A gas chromatographic method was developed which could separate the isomers isovaleric and 2-methylbutyric acid. Subsequent analyses revealed that most commercially available samples of these acids were cross-contaminated; however, one sample of each acid was found to be pure by this criterion. The growth response of seven strains of cellulolytic rumen bacteria (three strains of Bacteroides succinogenes, three strains of Ruminococcus flavefaciens, and one strain of R. albus) to additions of isobutyric, isovaleric, 2-methylbutyric, valeric, and combinations of valeric and a branched-chain acid was determined. Strains of B. succinogenes required a combination of valeric plus either isobutyric or 2-methylbutyric acid. Isovaleric acid was completely inactive. Either isobutyric or 2-methylbutyric acid was required for the growth of R. albus 7. Strain C-94 of R. flavefaciens grew slowly in the presence of any one of the three branched-chain acids, but a combination of isobutyric and 2-methylbutyric acids appeared to satisfy this organism's growth requirements. None of the individual acids or mixtures of straight- and branched-chain acids allowed growth of R. flavefaciens strain C1a which would approach the response obtained from the total mixture of acids. Further work indicated that all three branched-chain acids were required for optimal growth by this strain, although isovaleric acid only influenced the rate of maximal growth. Either 2-methylbutyric or isovaleric acid allowed growth of nearly the same magnitude as that of the positive control for R. flavefaciens B34b. The presence of acetic acid had little influence on the rate or extent of growth of any of the strains except R. albus 7, for which the extent of growth was markedly increased. Determination of the quantitative fatty acid requirements for the three B. succinogenes strains indicated that 0.1 mumole of valeric per ml and 0.05 mumole of 2-methylbutyric per ml permitted maximal growth. However, with isobutyric acid as the branched-chain component, strains A3c and B21a required 0.1 mumole/ml in contrast to S-85 which exhibited optimal growth at the 0.05 mumole/ml level. By use of mixtures of isobutyric and 2-methylbutyric acids, good growth of C-94 was obtained at concentrations of 0.1 and 0.01 mumole/ml, respectively. About 0.3 mumole/ml of each acid was required for satisfactory growth of C1a.

Animals↗

Different skin thinning potential of equipotent medium-strength glucocorticoids.

In this study, we investigated the effect of prednicarbate, mometasone furoate and betamethasone 17-valerate on total skin thickness over a treatment period of 6 weeks. The study was conducted as a double-blind, placebo-controlled randomized clinical trial with a confirmatory approach. The influence of these drugs on healthy human skin under non-occlusive conditions was assessed by measuring total skin thickness and epidermal thickness using 20 and 50 MHz sonography, respectively. Epidermal surface structure was evaluated using profilometry. Visual assessment addressed signs of atrophy and formation of telangiectasia. The reduction of total skin thickness induced by prednicarbate was clearly less than that caused by betamethasone 17-valerate and mometasone furoate. Prednicarbate led to a higher degree of skin thinning than vehicle. For technical reasons, epidermal thickness could not be reliably evaluated with 50 MHz sonography. Profilometry did not demonstrate any differences between treatments. Visible signs of atrophy or telangiectasia were detected in two subjects each upon betamethasone 17-valerate and mometasone furoate, but not upon prednicarbate or its vehicle. Prednicarbate is a topical glucocorticoid with an improved benefit/risk ratio, as it causes less skin atrophy than the equipotent betamethasone 17-valerate.

Administration, Topical↗

Thermodynamic analysis of product formation in mesophilic acidogenesis of lactose.

Thermodynamic analysis on the acidogenesis of lactose was performed to evaluate the different acidogenic patterns and mechanisms by using Gibbs free energy calculation. Batch acidogenesis of lactose was investigated by using an enriched culture at 37 degrees C, pH 5.5 and varied substrate levels. In addition to usual acidogenic products, i-butyrate, valerate, i-valerate, caproate, and propanol were also produced at a significant level. Thermodynamic analysis shows that valerate might be formed through the reaction requiring hydrogen as electron donor and consuming of propionate and carbon dioxide. Caproate was most likely produced directly from butyrate, hydrogen, and carbon dioxide. The minimum amount of Gibbs free energies needed to sustain isomerization of butyrate and valerate were approximately 5.7-5.8 and 4.5-4.6 kJ/mol, respectively. Propanol was produced from acetate, hydrogen, and carbon dioxide with a minimum amount of Gibbs free energy of 41.8-42.0 kJ/mol. Formation of butanol was controlled more by substrate level or population dynamics than by thermodynamics.

Alcohols↗

The effect of estrogen administration in vivo on the elemental composition of the intraluminal fluids of the seminiferous tubules, rete testis, and epididymis of the rat.

The maturation of spermatozoa in the epididymis is dependent upon the presence of androgens. This study examined the effects of androgen suppression by estradiol valerate on the elemental composition of the intraluminal fluids of the testis and epididymis. In the fluid from the caput epididymidis, the concentrations of sodium (106.1 +/- 3.4 to 182.8 +/- 16.9 mmol/1, P less than 0.01) and chloride (16.5 +/- 2.2 to 79.3 +/- 10.8 mmol/1, P less than 0.01) rose after treatment with estradiol valerate. By contrast, this treatment reduced the concentrations of phosphorus (63.7 +/- 1.6 to 47.8 +/- 3.2 mmol/1, P less than 0.01), sulfur (18.4 +/- 1.0 to 10.8 +/- 1.0 mmol/1, P less than 0.01), calcium (0.93 +/- 0.09 to 0.50 +/- 0.07 mmol/1, P less than 0.01), and magnesium (2.21 +/- 0.41 to 0.76 +/- 0.16 mmol/1, P less than 0.01). In the distal cauda epididymidis, the concentration of chloride rose after treatment with estradiol valerate (24.4 +/- 1.7 to 54.9 +/- 3.9 mmol/1, P less than 0.01), but the concentrations of the other measured elements (sodium, potassium, phosphorus, calcium, magnesium, and sulfur) were not altered by estrogen treatment. In rete testis fluid the concentration of phosphorus fell (2.00 +/- 0.30 to 0.67 +/- 0.12 mmol/1, P less than 0.01), while that of calcium rose (0.66 +/- 0.15 to 1.55 +/- 0.21 mmol/1, P less than 0.01). Estrogen treatment did not appear to affect the elemental composition of seminiferous tubular fluid or serum. Therefore, estradiol valerate had a marked impact on the elemental composition of luminal fluid only in the caput epididymidis--where sperm maturation is initiated--and a minor effect on that of cauda epididymidal fluid--in which mature spermatozoa are stored.

Animals↗

Comparison of the effect of different short chain fatty acids on the growth and differentiation of human colonic carcinoma cell lines in vitro.

The aim of this study was to compare the effects of acetate, propionate, butyrate, iso-butyrate, valerate, iso-valerate and caproate on cell growth and on the activities of alkaline phosphatase (AP) and dipeptidyl aminopeptidase IV (DPP IV) by three human colonic adenocarcinoma cell lines. In addition to butyrate, propionate and valerate inhibited cell proliferation of the three cell lines. The other SCFAs did not influence cell proliferation. AP and DPP IV activities were strongly stimulated by butyrate on two of the three cell lines. On HT-29, AP was strongly stimulated, however DPPIV expression remained undetectable. Propionate and valerate exhibited a weaker stimulation, the other SCFAs being ineffective. The effect of SCFAs on cell proliferation and differentiation clearly depends on the number of carbons and on the configuration of the basic structure of the molecule.

Alkaline Phosphatase↗

Effects of raloxifene, hormone therapy, and soy isoflavone on serum high-sensitive C-reactive protein in postmenopausal women.

OBJECTIVE: To compare the effects of raloxifene, estradiol valerate plus dienogest, and soy isoflavones (genistein) on serum concentrations of high-sensitive C-reactive protein in healthy postmenopausal women. METHODS: The 80 healthy postmenopausal women enrolled in the study were randomly allocated to receive 60 mg of raloxifene, 2 mg of estradiol valerate plus dienogest, 40 mg of genistein, or placebo (n=20 in each group). Blood samples were collected at the start of the study and at 3 and 6 months. Lipid profile was also determined. RESULTS: Only the group receiving estradiol valerate plus dienogest showed an increase in serum levels of high-sensitive C-reactive protein compared with baseline values and values in the control and other groups. All 3 treatments resulted in an increase in high-density lipoprotein cholesterol levels and a decrease in total, low-density, and very-low-density lipoprotein cholesterol levels. CONCLUSIONS: Estradiol valerate plus dienogest, but not raloxifene and genistein, increase serum high-sensitive C-reactive protein levels. All 3 treatments, however, have an estrogen-like effect on serum lipid profile.

C-Reactive Protein↗

Synthesis of polyhydroxyalkanoates from different short-chain fatty acids by mixed cultures submitted to aerobic dynamic feeding.

The production of polyhydroxyalkanoates from acetate and propionate by two mixed cultures well adapted to each of these substrates was evaluated. Sludge fed with acetate (A), produced a homopolymer of hydroxybutyrate (HB), whereas sludge fed with propionate (P) produced a copolymer of HB and HV (hydoxyvalerate). Switching the substrate feeds, propionate to sludge A and acetate to culture P, a terpolymer of HB, HV and hydroxymethylvalerate (HMV) was obtained with culture A and a copolymer of P(HB/HV) by sludge P. Regardless of the population used, the polymer yield and productivity were much higher for acetate than for propionate. Feeding a mixture of acetate and propionate, in equal parts, to both cultures resulted in an increase of HV units produced per C mol of propionate consumed, relative to the situation where only propionate was used. The individual use of butyrate and valerate by culture A was also studied. Butyrate produced a homopolymer whereas valerate was stored as a terpolymer of P(HB/HV/HMV). The polymer yields on acetate and butyrate were higher than those on propionate and valerate. The polymer productivity was higher for acetate and propionate than for butyrate and valerate. Results showed that the polymer composition, and consequently the polymer properties, could be manipulated by varying the volatile fatty acid feed composition and/or the population.

Acetic Acid↗

Bovine chromaffin cell cultures as model to study organophosporus neurotoxicity.

Based on the high level of phenyl valerate esterase activities, and in particular of neuropathy target esterase (NTE) found in bovine adrenal medulla, chromaffin cells culture have been proposed as an alternative model for the study of organophosphorus neurotoxicity. Organophosphorus-induced polyneuropathy is a syndrome related to the inhibition and further modification by organophosphorus compounds of NTE (a protein that displays phenyl valerate esterase activity resistant to mipafox and sensitive to paraoxon). Total phenyl valerate esterase activities found in homogenate, particulate and soluble fractions of bovine adrenal medulla were 5200+/-35, 5000+/-280 and 1700+/-260 mU/g tissue, respectively. Cultured chromaffin cells displayed a total hydrolysing activity of 41+/-5 mU/10(6) cells. Homogenates of bovine adrenal medulla displayed only about 6% of activity sensitive to paraoxon. Most of the phenyl valerate esterase activity inhibited by mipafox (a neuropathy inducing compound) was found in particulate fraction. Cultured chromaffin cells displayed kinetics of inhibition by mipafox similar to the kinetics displayed by homogenates of bovine adrenal medulla. We conclude that NTE could be assayed in this system by only using one inhibitor (mipafox) instead of two (paraoxon and mipafox). Also, the proposal is supported of using chromaffin cells as in vitro model for the study of the role of NTE and related esterases in organophosphorus-induced polyneuropathy.

Adrenal Medulla↗

Relative affinity of 17 alpha- and/or 21-esters and 17 alpha, 21-diesters of cortisol for a glucocorticoid receptor from rat thymocytes.

The affinity, relative to cortisol (1), of 17 alpha- and 21-esters and 17 alpha,21-diesters of cortisol for the glucocorticoid receptor of rat thymus cytosol was determined by a competitive binding assay which used [3H]dexamethasone. Esterification of the 21-hydroxy group of cortisol caused a loss of relative affinity to 0.046 for acetate and 0.32 for valerate. Esterification of the 17 alpha-hydroxy group resulted in an increase in relative affinity to 1.14 for acetate, 12.4 for butyrate, and 11.5 for valerate. Diesters had relative affinities which reflected both trends. Thus, the 21-acetate, 21-propionate, 21-butyrate, and 21-valerate of cortisol 17-acetate had relative affinities of 0.036, 0.093, 0.152, and 0.272. The 21-acetate, 21-propionate, and 21-butyrate of cortisol 17-valerate had relative affinities of 0.76, 1.17, and 1.33.

Animals↗

Severe hypertriglyceridemia and pancreatitis following hormone replacement prior to cryothaw transfer.

PURPOSE: A case of acute pancreatitis with severe hypertriglyceridemia occurred following use of intramuscular estradiol valerate during endometrial preparation for cryopreserved embryos. METHODS: A 30-year-old woman with primary infertility and a past history of well-controlled hypothyroidism, underwent endometrial development with intramuscular estradiol valerate in preparation for the transfer of cryopreservred embryos. RESULTS: Initial hospitalization, discontinuation of all estrogens, aggressive intravenous fluid hydration, and initiation of low-fat diet with additional gemfibrozil treatment resulted in complete resolution of all symptoms related to the pancreatitis including the hyperlipidemia. A subsequent cryothaw cycle using oral estradiol resulted in a viable pregnancy with only mild increases in the patient's triglyceride and cholesterol levels noted throughout her 38-week gestation. CONCLUSION(S): Estradiol valerate, a commonly used form of estrogen for endometrial preparation during cryothaw cycles, may cause severe hypertriglyceridemia and acute pancreatitis in certain predisposed individuals. Oral and transdermal estrogens should be the preferred method of endometrial preparation in patients at high risk for lipid metabolism disorders, such as patients with polycystic ovarian syndrome and familial hypertriglyceridemia. These estrogens are more rapidly metabolized and have a shorter half life compared to that of estradiol valerate.

Cryopreservation↗

Avidin and streptavidin ligands based on the glycoluril bicyclic system.

Glycoluril derivatives with a carboxylic acid side chain have been synthesized and shown to bind to both avidin and streptavidin. Introduction of a valerate side chain in glycoluril led to an increased binding to both proteins only when the valerate group was bound to a N atom and with the proper stereochemistry [(+)-enantiomer]. On the other hand, introduction of the valerate side chain either on the bridgehead carbon or on the N atom with the opposite stereochemistry [(-)-enantiomer] led to a decrease in binding constant compared with unsubstituted glycoluril. Direct spectrophotometric competitive titration of each protein with a racemic ligand allowed measurement of the enantioselectivity of the ligand-protein complexation, together with the binding constant of the two enantiomers. In the case of the N-substituted glycoluril, the extension of the side chain by one methylene group, from valerate to caproate, led to an increase in the binding constant to both proteins. Docking studies using AutoDock 3.05 have been performed in order to predict the binding modes of these ligands to streptavidin. The effect of the stereochemistry and the position of the side chain on the binding constant to streptavidin is discussed in view of the predicted binding modes.

Alkynes↗