Biomedical subjects

D C Collins

Publications and source records attributed to D C Collins.

At least 37 records · Page 2Linked to original sources

PubMed1995

Effect of diet on lignans and isoflavonoid phytoestrogens in chimpanzees.

Diphenolic compounds belonging to the classes of lignans and isoflavonoids have been identified in urine of man and animals, including the chimpanzee. Some of these compounds, formed by intestinal bacteria from plant lignans and phytoestrogens, have been shown in animal studies to exhibit biological activities that suggest they could function as cancer-protective compounds. The effect of diet on urinary excretion of these compounds in the adult male chimpanzee has been studied. It was found that the chimpanzees consuming their regular food excreted large amounts of the isoflavonoid phytoestrogens, equol (mean +/- SE) (127.5 +/- 34.0 nmol/mg cr.) and daidzein (20.7 +/- 9.0 nmol/mg cr.) and the lignan, enterolactone (14.1 + 3.5 nmol/mg cr.). Small amounts of the lignan, enterodiol, (0.4 +/- 0.2 nmol/mg cr.) were also excreted. On all other four test diets (high protein, high carbohydrate, high vegetable, and high fat), the excretion was less, particularly on a high fat diet where the excretion of all diphenolic compounds was reduced by more than 90% to a level observed in omnivorous human subjects or women with breast cancer. These results suggest that diet profoundly influences the excretion of both animal lignans and phytoestrogens in urine. Because non-human primates are particularly resistant to mammary and genital carcinoma on estrogen treatment, the present data suggest that the very high levels of phytoestrogens and lignans as found during exposure to the regular diet may partially account for why these primates are so resistant to hormonal manipulations to induce cancer.

Animals↗

PubMed1995

Inhibition of rat steroid 5 alpha-reductase (isozyme 1) by suramin.

In this study, we show the inhibition of rat steroid 5 alpha-reductase (isozyme 1) by suramin. The enzyme activity decreased in a dose-dependent manner as suramin concentrations increased with the calculated drug dose required for 50% inhibition (at 5 microM testosterone and 200 microM NADPH) being 13 microM. Suramin showed non-competitive inhibition of 5 alpha-reductase with respect to testosterone (KT1 = 2.4 microM) and competitive inhibition with respect to NADPH (KiNADPH = 220 nM). Furthermore, suramin and NADP+, but not NAD+, protected 5 alpha-reductase from labeling by 2-azido-NADP+, a photoactive probe which has recently been used to identify the NADPH binding domain of 5 alpha-reductase. These results suggest that suramin inhibits rat steroid 5 alpha-reductase (isozyme 1) at the level of NADPH binding to the enzyme.

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

PubMed1995

Application of a method for estimating day of ovulation using urinary estrogen and progesterone metabolites.

Longitudinal epidemiologic studies of menstrual and reproductive function are more informative if one can identify day of ovulation. We previously developed a method for estimating day of ovulation that is feasible for epidemiologic studies. The method relies on the relative concentrations of estrogen and progesterone metabolites in daily first-morning urine specimens and does not require creatinine adjustment. This paper describes results of applying this method to a large study with 724 menstrual cycles from 217 women. The method estimated a credible day of ovulation in 88% of cycles. Missing data accounted for most of the failures. When we excluded anovulatory cycles (1%) and cycles with missing data, the method estimated a day of ovulation in 97% of cycles. Variance in luteal phase length was small for our sample, suggesting that this method of identifying a day of ovulation introduces no more measurement error than when day of ovulation is determined by plasma luteinizing hormone (LH), the standard clinical method.

Adult↗

PubMed1994

Photoaffinity labeling of rat liver microsomal steroid 5 alpha-reductase by 2-azido-NADP+.

Preincubation of female rat liver microsomal preparations with [2'-32P]2N3-NADP+ followed by photolysis with UV light (254 nm) and analysis by SDS-PAGE/autoradiography showed incorporation of 32P into at least 3 major protein bands in the molecular weight range of 14-97 Kd. Labeling of a 26 kD band, the apparent molecular weight of 5 alpha-reductase in liver microsomes, was accompanied by a loss of enzyme activity, consistent with its covalent modification. The inclusion of 20-fold excess NADP+ (100 microM) completely inhibited the incorporation of [2'-32P]2N3-NADP+ and preserved the enzyme activity, whereas excess NAD+ (100 microM) failed to protect 5 alpha-reductase (5 alpha R) activity. Similar results were obtained with the detergent-solubilized form of 5 alpha R. Polyethylene glycol (PEG) fractionation of detergent-solubilized preparations of 5 alpha R showed that all the 5 alpha R activity could be recovered in the 6.5% pellet with a 3-4-fold increase in the specific activity. photolysis of this fraction with [2'-32P]2N3-NADP+ resulted in approximately 2-fold increase in 32P labeling of the 5 alpha R band. Increasing photolysis time and concentration of the [2'-32P]2N3-NADP+ indicated that the half-life for photoincorporation and the apparent Kd were 1.0 min and 2 microM, respectively. These results suggest that 2N3-NADP+ is an effective probe of the NADP(H) binding site of 5 alpha R, and is a useful marker during purification of the enzyme.

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

PubMed1994

3 Alpha-hydroxysteroid dehydrogenase activity in rat liver and skin.

3 alpha-Hydroxysteroid dehydrogenase (3 alpha HSD) is one of the main enzymes involved in the metabolism of the active androgen, dihydrotestosterone (DHT). 3 alpha HSD catalyzes the reversible reduction of DHT to 5 alpha-androstane-3 alpha, 17 beta-diol (3 alpha DIOL). The equilibrium of 3 alpha HSD reductive and oxidative activity is an important factor in the regulation of intracellular levels of DHT. In this study, we determined the kinetic characteristics of 3 alpha HSD in the subcellular fractions of female rat liver and abdominal skin. The enzyme expressed its activity in the cytosol and microsomal fractions of both of these tissues. It showed higher activity with the phosphorylated cofactors, NADPH and NADP, and was inhibited by indomethacin. The Vmax values of 3 alpha HSD in the cytosol were 10-fold higher than the Vmax values in the microsomes in both the liver and skin. In both tissues, the Km values with DHT as the substrate (reductive) were lower than the Km with 3 alpha DIOL as the substrate (oxidative). Although the Vmax values of the oxidative reaction were higher than the Vmax values of the reductive reaction in both liver and skin, the low Km values and the higher Vmax/Km ratio for DHT indicated that the reduction of DHT to 3 alpha DIOL was the favored reaction. The enzyme kinetics of 3 alpha HSD suggest that neither tissue accumulates DHT, but promptly converts it to 3 alpha DIOL.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxysteroid Dehydrogenases↗

PubMed1994

Sex hormone receptor binding, progestin selectivity, and the new oral contraceptives.

The desired biologic effect of progestins used in OCs is progestational activity. Undesired pharmacologic properties such as androgenic activity are not necessary for contraception and increase the potential for adverse effects. A selective progestin has progestational effects at relatively low concentrations or doses and androgenic effects at only relatively high concentrations or doses. The degree to which progestational activity is maximized and androgenic activity is minimized is a measure of a progestin's selectivity. The ratio of its affinity for progesterone receptors to its affinity for androgen receptors is the selectivity index. To minimize the androgenic side effects associated with the older progestins, the doses used in OCs have been reduced over the years. These dose reductions have decreased the potential for undesired androgenic effects but also have negatively affected cycle control. Three new progestins, norgestimate, desogestrel, and gestodene, have relatively greater affinity for progesterone receptors than for androgen receptors when compared with the older agents, permitting a reduction in androgenic side effects without the need for further dose reduction. Preclinical receptor-binding studies and animal pharmacologic studies have documented the higher selectivity indexes of these new progestins. Their higher ratios of progestational to androgenic activity provide the basis for the reduction in androgenic adverse effects observed with their clinical use.

Animals↗

PubMed1994

Sexual behavior of chimpanzees (Pan troglodytes): male versus female regulation.

We investigated the sexual behavior of 13 chimpanzees (Pan troglodytes) in 2 types of pair test in order to clarify the interaction of social variables with female hormonal state. The frequency of copulation in tests in which the partners were freely accessible to each other was related to the male's dominance over the female; copulation was less frequent and was related to social compatibility in tests in which the female controlled access. Copulation was related to female hormonal state in both types of test. The results demonstrate (a) an association between female hormonal state and sexual activity of chimpanzees, (b) the influence of social relationships on sexual interactions, and (c) the importance of focusing on female sexual behavior before copulation, rather than copulation per se, in research on sexual arousability of female primates.

Animals↗

PubMed1994

Triiodothyronine and estradiol increase the serum level of androstanediol glucuronide but do not influence androgen UDP-glucuronyl transferase activity in the female rat.

In this study, adult female rats were treated with either estradiol, testosterone or triiodothyronine (T3). The mean +/- SD for serum levels of androstane-3 alpha,17 beta-diol glucuronide (ADIOL-G) in rats injected with estradiol (31.1 +/- 6.1 nmol/l) and T3 (28.7 +/- 6.1 nmol/l) increased three-fold in comparison to the controls (9.2 +/- 3.6 nmol/l; p < 0.01). There was no significant increase in ADIOL-G levels in rats injected with testosterone (12.0 +/- 3.4 nmol/l) even though serum testosterone levels increased more than 17-fold (1.2 +/- 0.3 nmol/l; p < 0.01). Testosterone levels remained below the detection level of the assay (0.07 nmol/l) in the control and the estradiol and T3 treatment groups. Androgen UDPGT activity in liver microsomes was not altered by treatment with testosterone, estradiol or T3. However, the UDPGT activity for p-nitrophenol increased two-fold in estradiol and T3-treated females (p < 0.01), but was not significantly altered by testosterone treatment. These results suggest that the activity of androgen UDPGT in liver is not the limiting factor in the increased serum levels of ADIOL-G observed on treatment with estradiol and T3.

Androstane-3,17-diol↗

PubMed1994

Effect of a peripheral and a central acting opioid antagonist on the testicular response to stress in rats.

The possible involvement of opioid receptors in mediating the inhibitory effects of immobilization stress on testicular steroidogenesis was determined in adult male rats. Unstressed controls and animals exposed to 3 h of immobilization stress were injected subcutaneously with either vehicle or 1 or 10 mg/kg body weight (BW) of naloxone or naltrexone methobromide (NMB; an opioid receptor antagonist that does not cross the blood-brain barrier) at the beginning of and at 1.5 h of the stress period. Animals were sacrificed at 2 h (30 min after the second injection of antagonist) or 3 h (90 min after the second injection of antagonist) of stress. Plasma LH was not affected by stress, but 30 min after naloxone (1 or 10 mg/kg BW) injection, LH was elevated in both control and stressed rats above levels in vehicle-injected animals. By 90 min after naloxone injection, plasma LH had declined to levels comparable to those in vehicle-injected animals. NMB had no effect on plasma LH concentrations in either control or stressed rats. Three hours of stress reduced plasma testosterone (T) levels by 60% in vehicle-injected animals. This effect of stress on plasma T levels was antagonized by the 10 mg/kg BW dose of naloxone and 1 or 10 mg/kg BW of NMB. The ability of naloxone to reverse the effect of stress on plasma T levels was likely related to its ability to stimulate LH secretion, but NMB normalized plasma T values in stressed animals without altering plasma LH concentrations. Only the highest dose of NMB increased plasma T levels in unstressed control animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldehyde-Lyases↗

PubMed1993

Inhibition of angiogenesis by antiestrogens.

In this study, we have determined the ability of the partial estrogen antagonists, clomiphene, tamoxifen, and nafoxidine, and the pure estrogen antagonists, ICI 164,384 and ICI 182,780, to inhibit angiogenesis in the chick egg chorioallantoic membrane. All of the partial estrogen antagonists and the pure estrogen antagonist, ICI 182,780, showed significant angiostatic activity in a dose-related manner. The addition of up to 5-fold of 17 beta-estradiol to the disks containing clomiphene, tamoxifen, or ICI 182,780 did not alter the angiostatic activity of these antiestrogens. These novel findings show that the antiestrogens are effective inhibitors of angiogenesis. The finding that angiostatic activity is not altered in the presence of excess estrogens suggests that this activity is exerted via mechanisms other than their inhibition of estrogen action. This angiostatic activity may contribute to the therapeutic effect of antiestrogens in estrogen receptor-negative tumors.

Animals↗

PubMed1993

Effects of an oral contraceptive on sexual behavior of chimpanzees (Pan troglodytes)

Behavioral and physiological effects of a combined oral contraceptive (OC) were studied in chimpanzees for comparative purposes related to (i) the ambiguity surrounding the effects of OCs on the sexuality of humans, (ii) the close biological relationship between chimpanzees and humans, especially with respect to endogenous sex hormones and sexual behavior, and (iii) the relatively greater behavioral sensitivity of the chimpanzee to changes in sex hormone levels such as those that accompany the use of OCs. Two different types of pair tests and detailed behavioral assessments were used to differentiate the hormonal effects of female behavior from social effects imposed by the male. Anogenital swelling and copulation were reduced during OC cycles, but the effect of the OC on copulation was directly related to the social and sexual relationship of the pair during natural cycles. The more compatible and more frequently copulating pairs in the natural cycles continued to copulate during the OC cycles, albeit at reduced rates, whereas the less compatible and less frequently copulating pairs ceased copulating altogether when the female received the OC. There was no independent effect of the OC on ejaculation per se. Both male and female sexual initiative were reduced in the OC cycles, but female responsiveness to male sexual solicitations and direct copulatory attempts were not affected. Data indicate that despite generally adverse effects of the OC on certain physiological and behavioral dimensions of sexuality, social factors ultimately determined the degree of response to the OC.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Serum and urinary concentrations of sex hormones and genital swelling during the menstrual cycle of the gibbon.

The relationship between sex hormone concentrations and female genital swelling during the menstrual cycle in the monogamous gibbon was comparable with that of polygamous female primates, such as the chimpanzee, which live in multimale groups and have larger swellings. The data, therefore, support the hypothesis proposed by C. R. Carpenter more than 50 years ago, that the gibbon's genital swelling, like that of other female primates, reflects basic physiological processes associated with progress of the menstrual cycle. Genital swelling increased during the follicular phase with increasing concentrations of oestradiol and oestrone glucuronide, reached maximal swelling in association with the mid-cycle peaks in the oestrogens and LH and began detumescence with the initial increases in progesterone during the luteal phase. The data also suggest that the menstrual cycle of the gibbon is shorter than previously reported, since cycles of 19-22 days exhibited hormone patterns that are consistent with ovulation. The genital swelling of the female gibbon is a useful marker for monitoring progress of the menstrual cycle and the presumptive time of ovulation.

Animals↗

PubMed1993

Management and rehabilitation of distal radius fractures.

Distal radius fractures require precise medical treatment, therapeutic intervention during fracture immobilization, and specialized rehabilitation thereafter to ensure an optimal functional result. With an understanding of the mechanics of distal radius fractures, surgical intervention, and bone healing, the therapist can modify the therapy program according to the patient's individual needs. The therapeutic process is begun in the crucial stage of bone healing during fracture immobilization. By addressing edema reduction and early range of motion of the uninvolved joints, most problems can be avoided before cast or fixator removal. Rehabilitation following the immobilization period should focus on regaining wrist movements provided that earlier problems have been addressed properly. During the rehabilitative process, the therapist can incorporate scar management, modalities, joint mobilization, active and passive range of motion, splinting, and strengthening to maximize the patient's functional result.

Carpal Tunnel Syndrome↗

PubMed1992

Inhibition of angiogenesis by suramin.

In this study, we have determined the ability of suramin to inhibit angiogenesis in the chick chorioallantoic membrane. Suramin alone showed significant angiostatic activity in a dose-related manner. Suramin also potentiated the activity of the angiostatic steroids, cortisol-21-phosphate, 17 alpha-hydroxyprogesterone, tetrahydrocortisol, and tetrahydrocortexolone. The presence of heparin decreased the angiostatic activity of suramin. These results suggest that suramin may decrease tumor growth by inhibiting angiogenesis. These novel findings indicate that suramin, perhaps in combination with angiostatic steroids, may be the basis for important new therapeutic approaches for diseases of neovascularization.

Allantois↗

PubMed1992

Hormone levels and anogenital swelling of female chimpanzees as a function of estrogen dosage in a combined oral contraceptive.

A combined oral contraceptive consisting of ethinyl estradiol (EE2) in three dosages (50, 100, and 400 micrograms) and norethindrone (0.5 mg) was given to female chimpanzees to determine the effect on endogenous sex hormone levels and anogenital swelling. Serum levels of EE2 increased with increasing dosages of EE2, estradiol decreased, and luteinizing hormone, progesterone and testosterone were maintained at approximately midfollicular phase levels. Urinary levels of EE2 glucuronide increased with the increasing dosages of EE2, whereas estrone and pregnanediol glucuronide were essentially undetectable. The cyclic increase in female anogenital swelling was abolished when the norethindrone was combined with 50 micrograms of EE2 and relatively constant and low levels of swelling were recorded. Relatively constant but successively higher levels of swelling were recorded when the norethindrone was combined with the higher dosages of EE2. These effects of oral contraceptives on female genital tissues are relevant to our laboratory studies of sexual behavior in chimpanzees given oral contraceptives and could also have implications for women taking oral contraceptives.

Anal Canal↗

PubMed1991

Hormonal profiles of natural conception cycles ending in early, unrecognized pregnancy loss.

Loss of a conceptus early in development can be detected by very sensitive assays specific for hCG. We examined 20 menstrual cycles ending in early loss of a conceptus in order to identify hormonal correlates of loss. Each loss cycle was compared to a successful conception cycle in the same woman, using daily concentration of urinary estrone-3-glucuronide and pregnanediol-3-glucuronide (PdG). The estrone-3-glucuronide and PdG profiles in cycles of early pregnancy loss were very similar to those in successful conception cycles until late in the luteal phase. Early pregnancy loss was not related to a midluteal deficiency in PdG. hCG tended to be detected later in cycles of early pregnancy loss than in successful conception cycles, presumably indicating later implantation. Ten of the early pregnancy losses implanted after luteal-day-10; only one of the successful pregnancies implanted that late. The corpus luteum responded to the conception in only 2 of the 10 loss cycles with late implantation. In contrast, the corpus luteum responded in 8 of 10 loss cycles with normally timed implantation. The similarity of preimplantation hormonal profiles in cycles of early pregnancy loss and in cycles with successful conceptions suggests that most early losses in reproductively normal women do not result directly from deficiencies in ovarian steroid production.

Abortion, Spontaneous↗

PubMed1990

Sources of cholesterol for testosterone biosynthesis in murine Leydig cells.

The sources of cholesterol for testosterone production were investigated in freshly isolated murine Leydig cells. In vitro stimulation with human CG (hCG) (0.2 IU/ml) caused a 75-fold increase in testosterone production. Leydig cells contained approximately equal amounts of free and esterified cholesterol (7.8 vs. 8.7 micrograms/mg protein). The total cholesterol content of cells stimulated for 4 h with hCG was significantly decreased compared with unstimulated cells (8.4 vs. 17.6 micrograms/mg protein); both free and esterified cholesterol decreased by about 50%. In unstimulated Leydig cells incubated with [14C]acetate for 12 h, the majority of incorporated [14C] was found in free and esterified cholesterol, whereas, in the hCG-stimulated cells, 80% of incorporated 14C was in testosterone. The activity of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase after 4 h in hCG-stimulated cells was 20% higher than in unstimulated cells (115.5 vs. 84.4 pmol/mg protein.min). However, by 6 h, HMG-CoA reductase activity doubled in the hCG-stimulated compared with unstimulated cells. By 12 h, HMG-CoA reductase activity in hCG-stimulated cells was 4 times the preincubation level and 8 times the 12-h level in unstimulated cells. HMG-CoA reductase activity induced by hCG was blocked by aminoglutethimide, an inhibitor of the cholesterol side-chain cleavage enzyme. Lovastatin, a potent inhibitor of HMG-CoA reductase, had no effect on unstimulated or hCG-stimulated testosterone production during a 12-h incubation. Murine high density lipoproteins (mHDL) increased HMG-CoA reductase activity in both unstimulated (29%) and hCG-stimulated (20%) cells. During a 6 h incubation, mHDL increased hCG-stimulated testosterone production by 20%, but had no effect on unstimulated testosterone production. These results suggest that murine Leydig cells store enough cholesterol and cholesteryl esters to support testosterone production for at least 12 h in vitro. Although mHDL does not have a major stimulatory effect on testosterone biosynthesis, it may be involved in the regulation of de novo cholesterol synthesis.

Aminoglutethimide↗

PubMed1990

A potential primate model for bone loss resulting from medical oophorectomy or menopause.

This study examined the potential use of the GnRH agonist-treated female monkey as a model for bone loss after medical oophorectomy or the onset of menopause in women. Three female rhesus monkeys (13-16 yr of age) were treated continuously for 10 months with 25 micrograms/day GnRH agonist using osmotic minipumps. All three animals exhibited normal menstrual cycles before treatment. Within 5 weeks of the beginning of GnRH agonist treatment, serum progesterone and estradiol concentrations had fallen to low values and did not rise significantly during the remaining treatment period. The decline in ovarian steroidogenesis was correlated with a reduction in bone mineral density (BMD; bone mineral content/bone width) of the caudal vertebrae and humerus. The reduction of BMD of the caudal vertebrae occurred gradually. The downward trend was evident during the first 3 treatment months, but did not fall significantly below pretreatment levels until 9 months of GnRN agonist treatment. The overall decline in BMD for the caudal vertebrae was approximately 14% after 9 months of GnRH agonist treatment. The measured decline in BMD of the humorous was 11%. Serum osteocalcin levels rose more than 10-fold above pretreatment values between 4 and 7 months of GnRH agonist treatment before declining to levels that approached pretreatment concentrations between 8 and 10 months of treatment. Menstrual cycles were reinitiated within 4 weeks after the termination of treatment, as shown by luteal phase increases in serum progesterone concentrations. BMD of the humerus and caudal vertebrae remained subnormal 2 months posttreatment, but by 5 months had recovered to near-pretreatment values. These data suggest that ovarian hormone deprivation induced by GnRH agonist administration is associated with a decline in BMD in female monkeys, and that this animal model may be an excellent model for postmenopausal bone loss or bone reduction resulting from medical oophorectomy. The GnRH agonist-treated monkey also has the potential to be developed as a model for type I postmenopausal osteoporosis.

Amino Acid Sequence↗