PubMed Health⌕ Search

Biomedical subjects

J Fishman

Publications and source records attributed to J Fishman.

At least 109 records · Page 6Linked to original sources
PubMed1983

Naloxone, a specific opioid antagonist, reverses chronic idiopathic constipation.

Two patients with long-standing idiopathic chronic constipation, which responded only to large daily doses of laxatives and additional suppositories and enemas, were treated with the specific opioid antagonist, naloxone, on a single-blind crossover basis. Both patients responded to naloxone treatment, with increased passage of faeces and increased wet and dry faecal weight. Although naloxone is poorly absorbed after oral administration, there was a positive response during oral as well as intravenous treatment, suggesting that the primary effect of naloxone is at specific opiate receptor sites in the myenteric plexus and other neural and endocrine cells of the intestinal wall.

Administration, Oral↗
PubMed1983

Nutrition-endocrine interactions: induction of reciprocal changes in the delta 4-5 alpha-reduction of testosterone and the cytochrome P-450-dependent oxidation of estradiol by dietary macronutrients in man.

The in vivo biotransformations of drugs known to be metabolized by enzymes localized in the endoplasmic reticulum of liver can be greatly altered by diet in humans, as we have shown previously. Steroid hormones also are metabolized extensively by hepatic microsomal enzymes; therefore, we examined the possibility that testosterone and estradiol biotransformations, as assessed with radiolabeled tracer methods, could be influenced by dietary macronutrients. Normal males were fed a high-protein diet for 2 weeks, followed by a high-carbohydrate diet for an additional 2 weeks. The delta 4-5 alpha-reduction of testosterone was considerably diminished, while the cytochrome P-450-dependent hydroxylation of estradiol at the C2 position was substantially enhanced during ingestion of the high-protein diet as compared with the high-carbohydrate diet. These results indicate that dietary macronutrients can significantly alter major metabolic pathways for testosterone and estradiol in man. The mechanism by which reciprocal changes in the delta 4-5 alpha-reduction of testosterone and the cytochrome P-450-mediated oxidation of estradiol are produced by diets is not known. Similar changes in steroid delta 4-5 alpha-reduction and cytochrome P-450-dependent chemical oxidations have been observed in circumstances in which the mixed-function oxidase system in liver is induced by agents such as phenobarbital, hexachlorobenzene, dioxin, and polyhalogenated biphenyls. Thus, the alterations in steroid hormone metabolism produced by dietary macronutrients in man mimic those that can be produced by drugs and environmental chemicals.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1983

Effects of obesity on estradiol metabolism: decreased formation of nonuterotropic metabolites.

Obesity is associated with an increased incidence of reproductive dysfunction and estrogen-linked diseases. In the present study, we have examined the principal oxidative biotransformations of estradiol in 13 obese premenopausal females and 10 obese males compared to those in 9 premenopausal female and 15 male controls. These studies were carried out using a recently devised, sensitive radiometric method which permits the assessment of the total in vivo oxidative metabolism of estradiol at specific sites (i.e. 17 alpha, 16 alpha, or C-2) on the steroid molecule. Our results indicate that obesity (greater than 60% above ideal body weight) is associated with significant decreases in hydroxylation at C-2 in both sexes (P less than 0.001 for females and P less than 0.02 for males) and in oxidation at 17 alpha in premenopausal females (P less than 0.05) compared to that in age-matched, normal weight controls. Analysis of the plasma 3H2O specific activity curves suggested a slight decrease in the rate of 17-oxidation in obese subjects. The extent of hydroxylation at 16 alpha was not significantly affected by obesity. These metabolic alterations documented in obesity could result in a relative hyperestrogenic state, since, unlike the other estrogen metabolites, the 2-hydroxyestrogen compounds display relatively little peripheral estrogenic activity. This metabolic alteration on a prolonged basis might be contributory to the prevalence of certain hormonally related diseases in obese individuals.

Adult↗
PubMed1983

Inhibition of phasic but not tonic pituitary secretion by 2-hydroxyoestrone in the rat: evidence of action as an oestrogen antagonist.

Rats with 4-day oestrous cycles, implanted with intracardiac catheters, were injected with 2-hydroxyoestrone at noon on pro-oestrus and their plasma LH levels monitored at frequent intervals thereafter. A dose of 100 micrograms 2-hydroxyoestrone completely abolished the preovulatory LH rise in four out of ten animals tested, showing no effect in the six others. When an injection of 10 micrograms oestradiol 1 h before the 2-hydroxyoestrone administration was given all the rats showed an absence of the preovulatory LH surge, while it remained intact in the controls treated with oestradiol only. The principal metabolite of 2-hydroxyoestrone, 2-methoxyoestrone, exhibited no influence on the pituitary gonadotrophin release. Repeated injections of 100 micrograms doses of 2-hydroxyoestrone to long-term ovariectomized rats produced no change in plasma LH and prolactin levels. In animals primed with oestradiol benzoate, 2-hydroxyoestrone given 1-2 h after the priming dose blocked the phasic release of the pituitary hormones on the afternoon of the 2 subsequent days. The LH and prolactin surges in the primed animals, however, were not affected when the catechol oestrogen was injected 2 h before their appearance. These results indicate that in the cyclic rat exogenous 2-hydroxyoestrone inhibits the preovulatory LH surge when its administration is coincident with the preovulatory oestradiol rise. In the ovariectomized rat 2-hydroxyoestrone inhibits the oestrogen-dependent priming step but does not affect either the oestrogen-independent expression of the induced surges or the tonic secretion of these pituitary hormones. These results indicate a dissociation of central and peripheral activities in this oestradiol metabolite and suggest that this catechol oestrogen functions as an oestrogen antagonist in neuroendocrine events. Since catechol oestrogens can be formed in the brain these pharmacological responses may reflect physiological mechanisms.

Animals↗
PubMed1983

Abnormal estrogen conjugation in women at risk for familial breast cancer at the periovulatory stage of the menstrual cycle.

The present study was designed to establish whether women with a family history of breast cancer exhibit endocrine abnormalities which could be responsible for their increased risk for the disease. Plasma hormone levels were measured every second day throughout the menstrual cycle in 30 women at risk for familial breast cancer and in an equal number of matched controls. Thirteen of the 14 substances measured exhibited no differences between the two populations, but plasma androsterone sulfate was significantly lower in the high-risk subjects. Thirteen urinary hormones were measured every day throughout the cycle with only the mean estrone and estradiol glucuronide but not estriol glucuronide content being significantly lower in the high-risk subjects. A compensatory increase in the urinary estrogen sulfates was observed. Daily analysis of these differences showed that they were most pronounced in thry day throughout the cycle with only the mean estrone and estradiol glucuronide but not estriol glucuronide content being significantly lower in the high-risk subjects. A compensatory increase in the urinary estrogen sulfates was observed. Daily analysis of these differences showed that they were most pronounced in thry day throughout the cycle with only the mean estrone and estradiol glucuronide but not estriol glucuronide content being significantly lower in the high-risk subjects. A compensatory increase in the urinary estrogen sulfates was observed. Daily analysis of these differences showed that they were most pronounced in the periovulatory period of the cycle. These results suggest that the genetic risk for breast cancer is associated with an abnormality in estrogen conjugation at a specific time of the ovulatory cycle.

Androgens↗
PubMed1983

Scoring system for assessing the treatment of supracondylar fractures of the humerus.

This study follows up supracondylar fractures of the humerus in 41 children. Twenty-one boys and 20 girls were observed over an average period of 4.6 yr. The ages at the time of the fracture varied between 1 and 15 yr, the highest incidence occurring between 5 and 8 yr. Twenty-four patients were treated by closed reduction and long arm cast fixation, and 17 were handled by closed reduction after overhead skeletal traction. The children who were treated with skeletal traction had comparatively more-severe fractures. Although the results have no statistical significance, a greater range of motion was regained in the elbows treated by the skeletal traction method. Following treatment, none of the patients had complications from infection or from neurovascular problems. One of the problems this study posed was in comparing our work to similar published reports. We therefore developed a new scoring system for evaluating the results achieved in treatment of this type of fracture.

Adolescent↗
PubMed1983

6. Steroid metabolism in neuroendocrine structures. Specific and nonspecific components in the oxidative metabolism of estradiol by the male rat brain in vitro.

The oxidative transformation of estradiol at the C-2 and C-4 positions in the male rat brain was studied by the transfer of 3H into water from [2-3H]- and [4-3H]-estradiol. The nonenzymatic transformation at either site was linear with substrate concentration. The addition of pyridine nucleotide cofactors had no effect on the transformation at the C-4 site. The C-2 reaction was greatly enhanced by NADPH or NADH and exhibited the greatest velocity in the microsomal formation in the presence of NADH. The C-2 reaction exhibited saturation with respect to substrate and NADH with apparent KM of 1.82 microM and 0.34 mM respectively and Vmax of 81.3-76.3 pmol/mg protein/60 min. The reaction at C-4 failed to exhibit substrate saturation up to 30 microM. These data indicate that male rat brain estrogen hydroxylase is specific for the C-2 position, is NADH dependent and thus different from the corresponding liver enzyme. The reaction at C-4 in the brain tissues fails to exhibit enzymatic characteristics and the formation of 4-hydroxyestrogens in that tissue may be artifactual.

Animals↗
PubMed1982

The effect of estrogen priming of hypogonadal women on the release of gonadotropins and prolactin in response to 2-hydroxyestradiol.

We have previously shown that the administration of a 2-hydroxyestradiol (20H-E2) infusion (250 microgram/h x 4 h) to hypogonadal women resulted in a selective increase in the levels of circulating prolactin (PRL) without changes in LH or FSH. The present study concerns the effect of estrogen priming of hypogonadal women on the release of gonadotropins and PRL in response to an identical 20H-E2 infusion. Estrogen priming consisted of a 5 day course of orally administered ethinyl estradiol at a daily dose of 300 micrograms. Significant (P less than 0.05) inhibition of LH release was observed within 1 h of the onset of the 20H-E2 infusion reaching a nadir (-25 +/- 2%) by 3.75 h. The circulating levels of FSH remained unaltered for the duration of the 8 h study. In contrast, significant (P less than 0.05) increments in the release of PRL could clearly be detected after a lag period of 1.5 h reaching a peak (+91 +/- 11%) by 4 h. These and previous findings demonstrate that the inhibitory influence of 20H-E2 on gonadotropin secretion is conditional upon prior estrogen priming while the ability of 20H-E2 to stimulate the release of PRL is not.

Aged↗
PubMed1982

Formation of covalent adducts between cortisol and 16 alpha-hydroxyestrone and protein: possible role in the pathogenesis of cortisol toxicity and systemic lupus erythematosus.

The incubation of albumin with cortisol or 16 alpha-hydroxyestrone results in the formation of covalent steroid-protein adducts. The rate of adduct formation increases in the presence of sodium cyanoborohydride (NaCNBH3), indicating that the reaction proceeds nonenzymatically through a Schiff base intermediate. Under nonreducing conditions, a stable adduct forms with cortisol and 16 alpha-hydroxyestrone but not with estrone, which lacks a hydroxyl group adjacent to the reactive carbonyl. It is hypothesized that a Heyns rearrangement involving the adjacent hydroxyl group traps the Schiff base and produces a stable ketoamine adduct. The binding of 16 alpha-hydroxyestrone and cortisol to albumin is significantly inhibited by acetylsalicylic acid, which has been shown to acetylate an epsilon-amino group of a lysine residue in albumin. High-pressure liquid chromatography analysis of an acid hydrolysate of 16 alpha-hydroxyestrone-albumin shows that a product containing 16 alpha-hydroxyestrone coelutes with a standard prepared by reacting 16 alpha-hydroxyestrone with the epsilon-amino group of lysine. We propose that the formation of covalent steroid-protein adducts is a generalized phenomenon which may contribute to the pathological effects produced by elevated levels of certain endogenous steroids.

Acetylation↗
PubMed1982

Abnormal oxidative metabolism of estradiol in women with breast cancer.

The three dominant oxidative biotransformations of estradiol were examined in 10 normal women and 33 females with breast cancer by using a recently devised radiometric method. Estradiol tracers, labeled with 3H specifically in the 17 alpha, C-2, or 16 alpha position, were used to measure both the rate and extent of 17 beta-ol oxidation (the initial metabolic step) and the subsequent 2- and 16 alpha-oxidative reactions. The mean +/- SEM values for the extent of extradiol metabolism at these three specific sites for the extent of estradiol metabolism at these three specific sites were 76.9 +/- 5.3%, 31.1 +/- 4.0%, and 9.3 +/- 0.8%, respectively in normal subjects. Corresponding data in patients with breast cancer--i.e., 73.0 +/- 4.2%, 32.7 +/- 2.7%, and 14.9 +/- 1.5%--revealed a significantly greater extent of 16 alpha-hydroxylation in the latter population. Because the 16 alpha-hydroxylated compounds (including estriol) are themselves potent estrogens, these changes may have important hyperestrogenic consequences that could have a bearing on the etiology of the disease.

Adult↗
PubMed1982

Competition by estrogens for catecholamine receptor binding in vitro.

We have examined the ability of various steroids to compete for high-affinity binding of 3H-labeled ligands to catecholamine receptors in membranes prepared from rat cerebral cortex, striatum, and anterior pituitary. Ligands employed were: [3H]WB4101, [3H]prazosin, [3H]yohimbine, and [3H]clonidine (alpha-noradrenergic); [3H]dihydroalprenolol (beta-noradrenergic); [3H]spiperone and [3H]ADTN (dopaminergic). Only the 17 beta estrogens were effective and only binding of [3H]spiperone and [3H]ADTN in striatum and [3H]WB4101 and [3H]prazosin in cerebral cortex was reduced. Thus putative dopaminergic and alpha 1-noradrenergic sites alone appear to recognize estrogens. A slight competitive effect on [3H]spiperone binding to anterior pituitary membranes was also observed. Among the 17 beta estrogens tested, the most effective in all cases was the catechol estrogen 2-hydroxyestradiol (2-OHE2). The ability of 2-OHE2 (IC50 = 20-30 micro M) to inhibit ligand binding to alpha 1 receptors was comparable to that of norepinephrine (IC50 = 10-20 micro M), whereas for dopamine receptors in striatum and pituitary 2-OHE2 was an order of magnitude less effective than dopamine (IC50 = 12 micro M) in reducing binding of 3H ligands. Estradiol-17 beta and 2-hydroxyestrone were also able to inhibit binding, but the order of steroid potency was different for alpha 1 and dopaminergic receptors. Progesterone, testosterone, and corticosterone were without effect in all cases. These results show that there is specificity of steroid interactions with catecholamine receptors in the brain, both in terms of steroid structure and receptor type. The possible relevance of these interactions to neuroendocrine function is discussed.

Animals↗
PubMed1982

2-Hydroxyestrone suppresses and 2-methoxyestrone augments the preovulatory prolactin surge in the cycling rat.

The nonuterotropic metabolite of estradiol, 2-hydroxyestrone, administered at noon of proestrus to four-day cycling rats, abolishes the preovulatory prolactin rise in a large percentage of animals tested. In animals synchronized with exogenous estradiol, 2-hydroxyestrone universally induced a long delay in the prolactin surge. The principal metabolite of 2-hydroxyestrone, 2-methoxyestrone, given at noon of proestrus, significantly augments the magnitude of the preovulatory prolactin rise possibly by inhibiting the formation of endogenous 2-hydroxyestrogens in the brain. The results obtained are consistent with the concept of a physiological function for 2-hydroxyestrogens as estrogen antagonists in the CNS.

Animals↗