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Biomedical subjects

B Little

Publications and source records attributed to B Little.

At least 55 records · Page 3Linked to original sources
PubMed1981

In situ estradiol and progestin (R5020) localization in the vascularly separated and isolated hypothalamus of the rhesus monkey.

A neurosurgical procedure has been developed for vascular isolation of the hypothalamus-thalamus region of the rhesus monkey brain. Utilizing this preparation, the left and right halves of the hypothalamus were perfused simultaneously, but separately, with a dextran-blood solution. Radiolabeled steroids were directly perfused in the dextran-blood into either the left or right half of the hypothalamus. Studies with radiolabeled gonadal steroids indicate that the majority of the carotid circulation is confined to the hypothalamus-thalamus area in this brain preparation and the cross-circulation of labelled steroids between the left and right sides of the hypothalamus is less than 10%. The usefulness of the preparation is illustrated by an autoradiographic study of the in situ hypothalamic distribution of (3H)estradiol in ovariectomized rhesus monkeys and of the synthetic progestin(3H)R5020 in estrogen-primed, ovariectomized rhesus monkeys. The direct perfusion of the (3H) steroids into the hypothalamus greatly increases the sensitivity of such compared to systemic administration of the (3H) steroids. The perfusion of one-half of the hypothalamus with )3H) steroid and the other half with (3H) steroids. The perfusion of one-half of the hypothalamus with (3H) steroid and the other half with (3H) steroids. The perfusion of one-half of the hypothalamus with (3H) steroid and the other half with (3H)steroid plus radioinert steroids permits in 1 animal, acting as its own control, the examination of a saturable distribution of a gonadal steroid in the rhesus monkey hypothalamus.

Animals↗
PubMed1981

In situ subcellular distribution and metabolism of progesterone, estradiol and androstenedione in the vascularly separated and isolated hypothalamus of the female rhesus monkey.

A neurosurgical procedure has been developed for the vascular isolation of the hypothalamus-thalamus region of the rhesus monkey brain. The circulation to the left and right halves of the hypothalamus was also isolated and each half of the hypothalamus was perfused simultaneously, but separately, with a dextran-blood solution which contained radioactive gonadal steroids. The hypothalamus in situ efficiently converted [3H]androstenedione to [3H]estrone and this aromatization was inhibited by the presence of androsta-1,4,6-triene-3,17-dione (ATD) in the perfusate. [3H]Progesterone was metabolized predominantly to 5 alpha-pregnane-3,20-dione (5 alpha-DHP) and 20 alpha-hydroxypregn-4-ene-3-one (20 alpha-OHP). Subcellular fractionation of the hypothalamus after the in situ perfusion with [3H]-progestin or [3H]estradiol to the hypothalamus of estrogen-treated ovariectomized monkeys or oil-treated ovariectomized monkeys, respectively, indicated that the retention of [3H]estradiol in the nucleus was a saturable, limited-capacity phenomenon. No saturable subcellular distribution of [3H]progesterone or [3H]R 5020 was observed. This latter observation might be attributable to the presence of a progesterone receptor in too small a concentration to be detected by the methods used.

20-alpha-Dihydroprogesterone↗
PubMed1981

Tissue metabolism of estrogens in the female rhesus monkey.

The overall MCRs and [rho]BB values (fraction of infused precursor measured in blood as product) and individual tissue extractions and conversions were measured in the follicular and luteal phases of normal cycling female rhesus monkeys using constant infusions of [3H]estradiol ([3H]E2) and [14C]estrone ([14C]E1). During the infusions, blood samples were obtained from the femoral artery and veins draining the splanchnic tissue, kidney, head, arm, and uterus. The overall mean (+/- SE) MCR for E2 (214 +/- 17 liters/day) was significantly less than the MCR for E1 (295 +/- 13 liters/day). There were no differences in the MCR measured in the follicular or luteal phases of the cycle. The [rho]BB values were greater for the fraction of infused E1 measured in blood as product E2 [rho]E1, E2, BB; (0.25 +/- 0.02) than for [rho] E1, E2, BB (0.11 +/- 0.01). Neither value was affected by the time of the cycle. The extractions (that fraction of steroid measured in arterial blood entering a tissue which is metabolized and not measured as that steroid in venous blood draining the tissue) across the splanchnic tissues were the largest of the tissue extractions measured (0.63 +/- 0.05 for E2 and 0.73 +/- 0.10 for estrone). The arm, uterus, kidney, and head had lower extractions, and the extraction of E2 was always lower than that of E1, probably due to the specific globulin binding of E2. Interconversion of the estrogens occurred across each tissue bed but reflected, in general, only a small portion of the total extraction, especially for the splanchnic tissue. There was no apparent difference in any of the transtissue conversions measured in the follicular as compared to the luteal phase. The administration of pharmacological amounts of dexamethasone to three monkeys resulted in a marked increase in the MCR of estradiol and a slight decrease in the MCR of estrone. Individual tissue extractions and transtissue conversions showed no consistent alteration after dexamethasone.

Animals↗
PubMed1980

Malignant transformation of cultured rat hepatocytes by (+)- and (-)-trans-7,8-dihydro-7,8-dihydroxybenzo(a)pyrene.

Rat hepatocyte cultures (RL-PR-C) were tested with the (+)- or (-)-trans-7,8-dihydrodiol isomers of benzo(a)pyrene [B(a)P] and were assessed for growth inhibition, chromosomal damage, growth in soft agar, and tumor formation. Because early-passage cells have a noninducible low specific activity, aryl hydrocarbon hydroxylase parallel inhibition studies were performed on aryl hydrocarbon hydroxylase-inducible late-passage cultures. Early-passage cells exhibited little inhibition in the presence of B(a)P or either isomer. Comparable later-passage cells demonstrated inhibitory effects with B(a)P and the (+)- and (-)-trans-7,8-dihydrodiol metabolites. No treated cultures grew in soft agar, and the modal number of chromosomes was unaffected by carcinogen treatment. However, both (+) and (-) isomer-treated early-passage cells formed tumors in isogeneic animals, the (+) isomer being more efficient in this regard. These results indicate that noninhibitory doses of either the (+)- or (-)-trans-7,8-dihydrodiol isomer of B(a)P are nonetheless capable of malignantly transforming hepatocyte cells in vitro.

Animals↗
PubMed1979

Uterine metabolism of gonadal steroids during the menstrual cycle.

The metabolic clearance rate and uterine extraction of (3H)progesterone, (3H)estradiol, and (14C)estrone were studied at the time of hysterectomy in six women on or before day 12 of the menstrual cycle, in three women after day 12, and in one postmenopausal woman. The metabolic clearance rates of progesterone, estradiol, and estrone were in the same range as for normal women as previously reported by us. The uterine extraction for progesterone ranged between 12% and 37% on or before day 12 and 0% to 5% after day 12, and was 7.4% in the postmenopausal woman. The uterine extraction of estradiol was 0% to 25% on or before day 12, and 0%, 4%, and 22% after day 12 and was 18% in the postmenopausal woman. The uterine extraction of estrone was 7% to 24.5% on or before day 12 and 0% after day 12 and was 18% in the postmenopausal woman. The across-uterine interconversion of estradiol to estrone was 0% to 2.7% and of estrone to estradiol 0% to 2.6%. Both conversions appeared to be independent of the day of the menstrual cycle. The results suggest that the uterine metabolism of progesterone and estrone and perhaps estradiol is lower in the luteal phase of the cycle as compared to the follicular phase and that the conversion of estradiol to estrone may not be a major reaction of estradiol metabolism in the human uterus.

Adult↗
PubMed1978

The metabolic clearance rate and uterine metabolism and retention of progesterone and 20alpha-hydroxypregn-4-en-3-one during the secretion of uteroglobin in ovariectomized, steroid-treated rabbits.

The metabolic clearance rate (MCR) and in vivo uterine metabolism and retention of progesterone (P) and 20 alpha-hydroxypregn-4-en-3-one (20 alpha-OHP) during the uterine synthesis of uteroglobin in the rabbit have been studied. Oophorectomized rabbits with the uteri ligated received daily im injections of oil vehicle (C), 2 mg P/kg BW, or 2 microgram estradiol/kg BW. The MCR of [14C]P and [3H]20 alpha-OHP did not differ among treatment groups and was 260 +/- 30 and 270 +/- 33(SE) liters/day, respectively. Although the uterine tissue to arterial blood ratio of [14C]P differed between groups (E greater than C greater than P), the tissue to blood ratio of 20 alpha-OHP was the same for the three groups and was about 1. The uterine extraction of P was 32 +/- 6.2(SE)% and was the same for the three treatment groups. The uterine extraction of 20 alpha-OHP was significantly increased by estrogen treatment [33.4 +/- 6.0(SE)%] compared to the control [14.8 +/- 3.3(SE%)] or P[16.9 +/- 4.5(SE)%] groups. These studies indicate that the ability of exogenous 20alpha-OHP to stimulate uteroglobin secretion is probably mediated by its peripheral conversion to P. These studies also indicate the value of continuous infusion of radioactive steroids to evaluate tissue retention and metabolism in vivo.

20-alpha-Dihydroprogesterone↗
PubMed1977

The metabolic clearance rate, the brain extraction and distribution and the uterine extraction and retention of progesterone and R 5020 in estrogen-treated ovariectomized rabbits.

The metabolic clearance rate (MCR), uterine extraction, uterine retention and brain distribution of the synthetic progestin R 5020 and progesterone were studied in estrogen-treated ovariectomized rabbits. The MCR of R 5020 was 163+/-15 (SE) 1/day and was lower than that of progesterone. The uterine extraction of R 5020 (51.4+/-3.9 (SE)%) was greater than that of progesterone (33.7+/-7.7%) as was the uterine tissue:arterial blood ratio (28.1+/-4 vs. 7.3). The brain and pituitary retention and distribution of R 5020 and progesterone were the same and provided no evidence for a selective accumulation of a progestin in the pituitary or hypothalamus.

Animals↗
PubMed1976

The head extractions, brain and pituitary uptake and metabolism of progesterone and 5alpha-dihydroprogesterone in anesthetized, female rabbits.

Three days after ovariectomy adult female rabbits were injected intramuscularly with either 2 mug estradiol/kg b.w., 0.5 mg progesterone/kg b.w., 2 mug estradiol plus 0.5 mg progesterone/kg b.w., or oil vehicle daily for 5 days. On the sixth day the animals were anesthetized and given a continuous infusion of [14C]progesterone and [3H]5alpha-pregnane-3,20-dione (5alpha-DHP) for 4 h via the femoral vein. Head extractions, calculated from the difference in blood concentrations of radioactive steriods between the femoral artery and jugular vein, were in the range of 60-75% for both progesterone and 5alpha-DHP and were unaffected by the hormone treatments. Nine brain areas and the pituitary were analyzed for [14C]progesterone, [3H]5alpha-DHP and [14C]-5alpha-DHP. Generally, the brain and pituitary retention and distribution of [14C]progesterone and [3H]5alpha-DHP and the brain and pituitary metabolism of [14C]progesterone were unaffected by hormone treatments. In the cerebellum, progesterone treatment increased [14C]progesterone retention as compared to oil treatment. All tissues contained 2-7 times more [14C]progesterone than arterial blood concentrations. [3H]5alpha-DHP tissue: arterial blood concentrations ratios were much lower ranging from 0.9 to 1.78. [14C]progesterone and [3H]5alpha-DHP showed similar brain distribution with highest concentrations in the pons, pons reticulum and midbrain reticulum. All tissues converted progesterone to 5alpha-DHP, but only the cerebellum contained more [14C]5alpha-DHP than [14C]progesterone.

20-alpha-Dihydroprogesterone↗
PubMed1975

In vivo aspects of progesterone distribution and metabolism.

The end-organ response of any hormone is the result of many factors which precede the event, including biosynthesis, secretion, transport, distribution, and metabolism. These factors vary among different species. The metabolic clearance rate (MCR) of progesterone varies between 40 and 180 L./day/Kg. in man (60 to 70), monkey (40 to 50), rabbit (55 to 60), sheep (110), rat (120), and guinea pig (180). Major sites of clearance include liver, brain, and uterus. Specific metabolites of progesterone include 20 alpha-hydroxypregn-4-en-3-one (20 alphaOHP) and alpha-pregnan-3,20-dione (5 alpha-DPH). Liver, brain, and uterine clearances, extractions, and conversions of progesterone to these metabolites have been studied in various species under apparent steady-state conditions. A specific hormone action of progesterone, the appearance of uteroglobin in the rabbit uterus, has also been studied in varying horomonal states (estrogen, estrogen plus progesterone, and progesterone alone). These have all been used as examples of progesterone distribution and metabolism.

Animals↗