PubMed Health⌕ Search

Biomedical subjects

B H Shapiro

Publications and source records attributed to B H Shapiro.

At least 55 records · Page 3Linked to original sources
PubMed1991

Sex differences in the ultradian pattern of plasma growth hormone concentrations in mice.

Ultradian patterns of plasma GH concentration were determined in adult male and female mice. Serial blood samples were collected every 15 min over 8 h through surgically placed chronic indwelling right atrial catheters and assayed for GH content by an homologous radioimmunoassay. In both sexes, GH concentrations fluctuated episodically from baseline values that were often in the range of 2 micrograms/l which approached the limit of assay sensitivity, to peak values sometimes reaching 100 micrograms/l. Male mice, however, demonstrated a regular periodicity of GH peaks approximately every 2.5 h with interposed stable baseline concentrations that were significantly longer in duration than in females. The absence of extended baseline concentrations in females reduced cycle length to an average of 1.4 h and significantly increased the overall mean GH concentration. The duration, height and area of GH peaks and the average concentration between peaks were comparable in males and females. Sexual dimorphism in the ultradian patterns of serum GH concentrations have been shown in both mice and rats to regulate the expression of several sex-specific phenotypes. Comparing endogenous GH patterns in mice and rats demonstrates that males of both species have less frequent peaks than females over the same interval of time. This separation of GH peaks appears to be an essential element for the expression of masculine GH-dependent traits.

Activity Cycles↗
PubMed1990

Sex steroid changes in porcine cystic ovarian disease.

Ten sex steroids were measured in the peripheral serum and ovarian follicular fluid of female pigs with or without cystic ovarian disease. In general, progestin, especially progesterone, accumulated excessively in the fluid contained in cystic compared with normal follicles. Nonluteinized cystic follicles contained up to four times the progesterone concentration found in large normal preovulatory follicles. Levels of this steroid increased with luteinization of cystic follicles to as much as 10 times those found in large preovulatory follicles. In contrast, the concentration of follicular fluid androgens and estrogens in cystic follicles were, at best, barely detectable (5 to 10 pg/ml). These results are indicative of a steroidogenic blockade in the conversion of C21 progestin to C19 androgens and C18 estrogens in the cystic follicles. In spite of an enormous accumulation of follicular progestin and subnormal concentration of androgens and estrogens, circulating levels of these hormones in pigs bearing cystic ovaries were in the normal range for cycling sows. Clearly, the hormonal abnormalities in the cystic follicles are not reflected in the serum profiles of these steroids.

Androgens↗
PubMed1990

Depletion of serum growth hormone in adult female rats by neonatal monosodium glutamate treatment without loss of female-specific hepatic enzymes P450 2d (IIC12) and steroid 5 alpha-reductase.

The sexually dimorphic profiles of pituitary GH secretion play a key role in regulating the expression of several sex-dependent and developmentally controlled P-450 enzymes in rat liver. Current models for P-450 regulation by GH, however, are primarily based on hypophysectomy and GH replacement experiments. The present study examines the effects on hepatic P-450 expression of neonatal injections of monosodium glutamate (MSG), which allows for the nonsurgical suppression of adult GH levels. Furthermore, the levels of other pituitary-dependent hormones, such as testosterone and estradiol, are largely unchanged in the MSG-treated rats. Although hypophysectomy and GH replacement experiments have previously demonstrated that expression of the female-specific hepatic enzymes P-450 2d (gene product IIC12) and steroid 5 alpha-reductase is strikingly dependent on continuous GH exposure, neither enzyme was decreased in adult female rat liver after the elimination of plasma GH (less than 2 ng/ml) by neonatal MSG treatment. Moreover, although the loss of circulating GH appears to be largely responsible for the more than 10- to 20-fold elevation of the male-specific hepatic P-450 forms 2a (gene product IIIA2) and RLM2 (gene product IIA2) in hypophysectomized female rats, no such elevation of the male-specific P-450s was observed in the GH-deficient MSG-treated female rats. In contrast, the female-predominant forms P-450j (gene product IIE1) and 3 (gene product IIA1) were both elevated in adult rat liver after neonatal MSG treatment, in agreement with earlier hypophysectomy studies and demonstrating the suppressive effects that GH can exert on expression of these P-450 forms. Thus, although MSG and hypophysectomy both produce GH depletion, the responsiveness of the hepatic P-450s to these endocrine manipulations differs, allowing for an expanded understanding of the role of GH in P-450 expression.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1989

Growth hormone regulation of hepatic drug-metabolizing enzymes in the mouse.

Hepatic microsomal hexobarbital hydroxylase and aminopyrine N-demethylase activities increased in adult male mice following hypophysectomy to female-like levels, eliminating the normal sexually dimorphic pattern of these enzymes. Exogenous growth hormone replacement (0.08 I.U./100 g body weight/day) re-established the lower masculine activities only when administered subcutaneously once every 12 hr. Enzyme activities remained elevated at female-like levels when the same total dose of growth hormone was infused continuously using osmotic pumps or was injected once every 6 hr. These data suggest that, despite the reversed orientation of sex differences in hepatic drug-metabolizing enzymes between rats and mice (i.e. higher enzyme activities in female mice and male rats), the basic hormonal regulatory axis is similar in the two species. Cyclic fluctuations of systemic growth hormone concentrations masculinize kinetic parameters of hepatic hexobarbital hydroxylase and aminopyrine N-demethylase in both species. Rats and mice differ in that these similar hormonal signals lower the apparent Vmax in male mice, while markedly increasing the enzyme activities in male rats. It appears more likely, therefore, that species- and sex-specific differences in the total hepatic cytochrome P-450 isoenzyme populations produce the reversed sex-dependent pattern of hexobarbital hydroxylase and aminopyrine N-demethylase.

Animals↗
PubMed1989

Serum androgen levels in senescent Cr1:CD-1 (ICR)BR mice: effects of castration and testosterone treatment.

Serum levels of dehydroepiandrosterone, androstenedione, testosterone, and dihydrotestosterone were measured in intact, orchiectomized and orchiectomized-androgen-treated CD-1 mice. Although dehydroepiandrosterone was not detectable in the serum of old mice, approximately half of the very substantial serum concentration of this hormone found in the mature mice appeared to be of adrenal origin. In contrast to dehydroepiandrosterone, serum levels of testosterone and, when detectable, the other androgens, were the same in mature and senescent intact males. Serum levels responded similarly to castration and testosterone replacement. Seminal vesicle weights reflected the similar serum androgen levels found in both age groups. The results indicate that there is neither an age-associated decline in the serum concentration of testosterone nor an apparent alteration in the hepatic and/or peripheral metabolism of testosterone in aging CD-1 male mice.

Aging↗
PubMed1989

Signalling elements in the ultradian rhythm of circulating growth hormone regulating expression of sex-dependent forms of hepatic cytochrome P450.

Neonatal male rats were treated with monosodium glutamate (MSG) at either 2 or 4 mg/g BW on alternate days during the first 10 days of life. As adults, the 4 mg MSG-treated rats displayed the obesity, growth retardation, and reduced pituitary weights that typify this syndrome. These animals had no detectable plasma GH as determined from serial blood samples taken every 20 min for 8 consecutive h. Associated with this loss of circulating GH was an induction of the female-specific hepatic cytochrome P450 2d (gene IIC12) and the disappearance of the male-specific form of cytochrome P450 2c (gene IIC11). The catalytic activities of cytochrome P450 2c (i.e. androgen 16 alpha- and 2 alpha-hydroxylase), sex-dependent hexobarbital hydroxylase and total cytochrome P450 were similarly feminized. Rats exposed to the 2-mg dose of MSG were also obese, but their growth rates and pituitary sizes were not as severely affected as in the 4 mg MSG-treated rats. Circulating GH in these lower dosed males was secreted in a pulsatile pattern similar to that in normal males, except that the pulse amplitude was reduced as much as 90%. In spite of this profound decline in GH peak heights in the 2 mg MSG-treated males, liver metabolism was characteristically masculine. That is, female-specific cytochrome P450 2d remained undetectable, while the male forms of cytochrome P450 2c, 2a (gene IIIA2), and RLM2 (gene IIA2), their respective catalytic steroid hydroxylase activities, and associated sex-dependent drug-metabolizing enzymes were expressed at the level of or greater than that in normal males. Thus, while an ultradian pulse of circulating GH is necessary for the characteristically masculine profile of sex-specific forms of hepatic cytochrome P450, neither the amplitude of the secretory peaks nor their total GH content is critical, and these can be greatly reduced from the normal male levels.

Adrenal Glands↗
PubMed1988

Selective androgen insensitivity of hepatic drug-metabolizing enzymes in senescent mice.

The normal sexual dimorphism in murine hepatic hexobarbital metabolism (i.e. females greater than males) was found to be absent in senescent animals. Hexobarbital metabolism, expressed as microsomal activity of hexobarbital hydroxylase and hexobarbital-induced sleep time, in senescent male mice was similar to that in females, but significantly greater than that found in young adult males. No age-related changes in hexobarbital metabolism were observed in intact females. In addition, experiments involving gonadectomies and testosterone administration indicated that both male and female senescent mice were insensitive to the normally repressive effects of androgens on hexobarbital hydroxylase. In contrast, the sexual dimorphism in the activity of p-nitrophenol UDP-glucuronosyltransferase was maintained in the senescent mice as well as the usual responsiveness to testosterone regulation. Furthermore, the growth-promoting effects of androgen on the kidneys and seminal vesicles were similarly expressed in young and old mice. Thus, our results suggest the development of an age-dependent and selective insensitivity of hexobarbital hydroxylase to androgenic regulation in the aging mouse.

Aging↗
PubMed1988

Prospective study on the sexual development of male and female rats perinatally exposed to maternally administered cimetidine.

Cimetidine, a widely prescribed, potent histamine H2-receptor antagonist, is unrelatedly a mild antiandrogen. Since perinatal androgens are essential for normal masculine imprinting, we wanted to determine if maternally administered cimetidine interfered with the offspring's reproductive development. Cimetidine was administered in the mothers' drinking water at several levels reflecting both human and rat therapeutic-like doses from day 17 of gestation through day 7 of lactation. Except for the highest dose of cimetidine (4.0 mg/ml drinking water) the drug had no effect on the dams' food and water consumption or body weight gain. In general, feminine sexual development as measured by pubertal onset, reproductive organ weights and adult estrous cyclicity, was unaffected by perinatal exposure to cimetidine. Similarly, early exposure to the drug had little effect on masculine sexual development. The developmental profile of serum dehydroepiandrosterone, androstenedione, testosterone and 5 alpha-dihydrotestosterone when measured at 1, 4 and 18 weeks of age, was unaffected by perinatal exposure to cimetidine. Furthermore, serum androgen concentrations and seminal vesicle weights following orchiectomy and androgen replacement were the same in control and cimetidine-exposed rats. In contrast, pituitary weights of adult males exposed to maternally administered cimetidine appeared to be insensitive to androgen regulation. However, taken in totality, our results do not support the concept that cimetidine is a reproductive teratogen.

Androgens↗
PubMed1988

Correlation of follicular steroid hormone profiles with ovarian cyclicity in sows.

Ovaries were obtained from sows immediately after slaughter and were morphologically assigned to different stages of the ovarian cycle. Follicular fluid contained in the predominating follicles was analysed for ten steroid hormones by a multiple, simultaneous radioimmunoassay technique. The steroids measured were pregnenolone, progesterone, 20 alpha-dihydroprogesterone, 17 alpha-hydroxyprogesterone, androstenedione, 5 alpha-dihydrotestosterone, dehydroepiandrosterone, testosterone, oestrone and oestradiol-17 beta. The concentrations of the steroids remained relatively low during the luteal stages until the mid-follicular stage when ovaries contained predominantly small to medium-sized (less than 5.0 mm in diam.) follicles. With the exception of 5 alpha-dihydrotestosterone concentrations, which remained low regardless of the size of the follicles or the stage of the cycle, the concentrations of all the steroids were significantly elevated in the transition from the mid- to late follicular stage, a period when the ovaries contained mainly large (6-10 mm diam.) follicles. Follicles at the ovulatory stage exhibited a profound decline in the concentrations of androgens and oestrogens. In contrast, the magnitude of decline in the levels of 3 progestagens, i.e. pregnenolone, progesterone and 17 alpha-hydroxyprogesterone, was much less than that for androgens and oestrogens, while the concentration of 20 alpha-dihydroprogesterone was actually elevated in the ovulatory follicles. The present results agree with those of earlier studies which measured fewer steroids in follicles obtained by repeated and sequential laparotomies of sows during spontaneous cycles. In contrast, these hormone results differ from those using the PMSG/hCG-stimulated ovary, suggesting that such ovaries may not be a completely valid model for ovarian steroid hormone metabolism in the normally cycling sow.

Animals↗
PubMed1988

Repetitive blood sampling in unrestrained and unstressed mice using a chronic indwelling right atrial catheterization apparatus.

A re-usable mobile catheterization apparatus was developed that permits multiple blood samples to be obtained from nonrestrained and unanesthetized mice. The collection end of the catheter is located outside the cage allowing the mouse to remain completely undisturbed prior to and during blood collection. The apparatus was used in adult mice surgically fitted under pentobarbital anesthesia with right atrial silastic catheters. Sample volume and collection frequency are easily controlled without subjecting the animal to repetitive trauma. Low plasma corticosterone concentrations confirmed the nonstressful quality of the technique. Full catheter patency in mice averaged 21.5 days. The tethering apparatus design was easily upscaled to accommodate use in adult rats.

Animals↗
PubMed1987

Aberration of heme and hemoprotein in aged female rats.

The magnitude and duration of drug action is determined partially by the activity of the drug metabolizing enzyme systems in the liver. The pharmacological effectiveness of many drugs is altered during the aging process. In this study, the regulation of heme metabolism and hemoprotein content was examined in livers of aged female rats. The activities of hexobarbital hydroxylase and aniline hydroxylase, indicators of mono-oxygenase function, were decreased in aged rats by 31% and 24%, respectively, as compared to values in young rats. This was accompanied by a proportional decrease in the level of cytochrome P-450 (26%). Additionally, the activity of delta-aminolevulinic acid synthetase (ALA-S), the rate-limiting enzyme in heme synthesis, and the microsomal concentration of heme were also decreased by 33% and 26%, respectively, in these animals. In contrast, the basal activity of microsomal heme oxygenase (MHO), the rate-limiting enzyme in heme degradation, and the percent heme saturation of tryptophan pyrrolase (TPO), a sensitive indicator of changes in the availability of heme in the "regulatory" heme pool, were increased by (87%) and (31%), respectively, in the aged rats. The serum concentration of bilirubin, an indicator of erythrocyte breakdown and/or liver function was likewise increased in these animals. In view of these findings, we suggest that the high activity of MHO and the low level of ALA-S may be a significant causative factor for the decreased microsomal concentration of heme, cytochrome-P-450 and its dependent monooxygenase activities in senescent female rats.

5-Aminolevulinate Synthetase↗
PubMed1987

Developmental profile of serum androgens and estrous cyclicity of male and female rats exposed, perinatally, to maternally administered phenytoin.

Pregnant rats were treated, daily, with either 10, 50 or 100 mg/kg of phenytoin-Na from day 17 of gestation through postpartum day 7. The male and female offspring exposed to the 2 higher doses of phenytoin had smaller body weights at birth than the diluent-treated rats, and this subnormal body weight gain persisted throughout the life of the affected animals. In contrast, the anticonvulsant produced no adverse effects on the developmental profile of serum androstenedione, testosterone and dihydrotestosterone or estrous cyclicity in the exposed male and female offspring, respectively. In spite of the normal concentrations of serum androgens, the seminal vesicles of the adult rats exposed to the 50 and 100 mg/kg doses of phenytoin were significantly smaller than the diluent-treated males.

Androgens↗
PubMed1987

Strain independent elevation of hepatic mono-oxygenase enzymes in female mice.

1. Hepatic microsomal drug metabolizing activity was compared in male and female AL/N, Balb/c, Balb/cJ, CD-1, C57BL/6J, C57BL/10J, DBA/2, and DBA/2J mice. 2. Cytochrome P-450-dependent hexobarbital hydroxylase and aminopyrine N-demethylase activities were sexually dimorphic with apparent maximal velocities consistently higher in females. Hexobarbital-induced sleeping times were greater in males, corresponding to their lower hepatic mono-oxygenase enzyme activities measured in vitro. 3. No murine sex differences were observed for the hydroxylation of aniline, while UDP-glucuronyltransferase activity was strain dependent with either no sexual dimorphism or higher activities in males. 4. Testectomy resulted in an elevation of hepatic hexobarbital metabolism to female levels in all strains examined. Thus, decreased hepatic cytochrome P-450-dependent xenobiotic metabolism in adult male mice results from the suppressive effects of gonadal androgens. 5. Sexually dimorphic patterns of hepatic hexobarbital and aminopyrine metabolism in adult mice are opposite in orientation and lower in magnitude than the well established relationship in rats in which these same substrates are metabolized at a rate 3 to 5 fold higher in intact males as compared to females or gonadectomized males.

Animals↗
PubMed1986

Persistent defects in the hepatic monooxygenase system of adult rats exposed, perinatally, to maternally administered phenytoin.

Phenytoin is one of the most commonly used anticonvulsants in pregnant epileptic women. Unrelatedly, the drug is also an inducer of hepatic drug metabolizing enzymes. Considering these facts, we wanted to determine if maternal treatment with therapeutic-like doses for the rat of phenytoin would produce long-term defects in the metabolism and action of drugs in the dams' adult offspring. We found that peripartum exposure to phenytoin resulted in a significant depression in the maximal velocities of hepatic microsomal aminopyrine N-demethylase in the 28-day-old male and female offspring. When the animals were 4-to-5-month old adults, the maximal velocities for the demethylase and hexobarbital hydroxylase remained subnormal in the males but were elevated in the females exposed to the highest therapeutic-like dose of phenytoin. Hexobarbital-induced sleeping time measurements were in agreement with enzyme kinetic analyses. Lastly, the hepatic monooxygenases of the adult male and female rats exposed, perinatally, to all but the lowest dose of phenytoin, were much less responsive to the inductive effects of several low doses of phenobarbital. The results suggest that levels of phenytoin that may be therapeutic for the mother can produce defects in the developing hepatic monooxygenase system of the perinates, which can then permanently affect drug metabolism and action in adulthood. Furthermore, by disrupting the development of hepatic enzyme induction mechanisms, perinatal exposure to phenytoin may irreversibly alter an important homeostatic mechanism that is normally responsive to daily exposure to low levels of various endogenous and exogenous inducing agents.

Aminopyrine N-Demethylase↗
PubMed1985

Pituitary-dependent masculinization of hepatic hexobarbital hydroxylase in Crl:CD-1(ICR)BR mice.

The sexual dimorphism in hepatic drug metabolism found in Crl:CD-1 mice is due to the normally repressive effects of testicular androgens on the activities of hepatic monooxygenases. The ability of testosterone to elevate the Michaelis constant (Km) and reduce the maximum velocity (Vmax) of hepatic hexobarbital hydroxylase is dependent upon the pituitary, so that in the hypophysectomized mouse androgens have no repressive effects on the activities of hepatic monooxygenases.

Animals↗