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Biomedical subjects

J A Canick

Publications and source records attributed to J A Canick.

17 recordsLinked to original sources
PubMed1992

Prenatal screening for Down's syndrome with use of maternal serum markers.

BACKGROUND: Approximately 35 percent of all cases of Down's syndrome in fetuses can be detected by measuring maternal serum alpha-fetoprotein during the second trimester in the general population of pregnant women. Recent case-control studies indicate that this detection rate could be approximately doubled by measuring serum levels of unconjugated estriol and chorionic gonadotropin, which are abnormally low and abnormally high, respectively, in women carrying fetuses affected by Down's syndrome. METHODS: We prospectively screened 25,207 women and adolescents in the second trimester of pregnancy and assigned each a risk of fetal Down's syndrome with an algorithm that took into account measurements of all three serum markers in combination with maternal age. On this basis, 1661 subjects (6.6 percent) were initially assigned a second-trimester risk of fetal Down's syndrome of at least 1 in 190, and 962 (3.8 percent) were offered amniocentesis for chromosomal analysis after verification of gestational age. Gestational age was determined on the basis of the first day of the last menstrual period or, when available, by ultrasonography. RESULTS: Among the 760 women and adolescents who chose amniocentesis, 20 cases of fetal Down's syndrome were detected, along with 7 other chromosomal disorders. There was 1 additional case of fetal Down's syndrome among the 202 women who chose not to have amniocentesis. The rate of detection of Down's syndrome was thus 58 percent (21 of 36 expected cases), and the frequency of identifying a fetus with Down's syndrome in women undergoing amniocentesis was 1 per 38 amniocenteses (95 percent confidence interval, 1 in 25 to 1 in 62). CONCLUSIONS: Measuring serum alpha-fetoprotein, chorionic gonadotropin, and estriol is more effective in screening for fetal Down's syndrome than measuring maternal serum alpha-fetoprotein alone. Such an expanded protocol can readily be incorporated into existing prenatal screening programs.

Adolescent↗
PubMed1992

Prospective intervention trial of a screening protocol to identify fetal trisomy 18 using maternal serum alpha-fetoprotein, unconjugated oestriol, and human chorionic gonadotropin.

Two prenatal centres in New England, routinely using a screening protocol for fetal Down syndrome that included maternal serum alpha-fetoprotein (AFP), unconjugated oestriol (uE3), and human chorionic gonadotropin (hCG) measurements in combination with maternal age, adopted a separate screening protocol for trisomy 18. That protocol identified a pregnancy as being at high risk when AFP, uE3, and hCG measurements all fell at or below specified cut-offs (0.75, 0.60, and 0.55 multiples of the median, respectively), regardless of maternal age. Among the first 19,491 women screened, 98 (0.5 per cent) were found to have values which placed them in the high-risk category. Four of these women were subsequently found not to be pregnant. In two others, samples from non-pregnant individuals were found to have been incorrectly submitted for analysis in place of the samples from the pregnant women. All of the remaining 92 women were counselled and offered amniocentesis and fetal karyotyping. Eighty-eight (96 per cent) accepted. Karyotypes or birth outcomes were available on all 92 pregnancies. Six cases of trisomy 18 and one case of Turner syndrome were identified by karyotype. One case of trisomy 18 was identified for every 14 unaffected pregnancies offered amniocentesis. In the present prospective study, an estimated 85 per cent of the cases of trisomy 18 were identified. However, given the small number of cases (six), the 95 per cent confidence interval for the detection rate is broad (40-95 per cent).

Adult↗
PubMed1992

Steroid sulfatase in the human ovary and placenta: enzyme kinetics and phosphate inhibition.

In 5 placental homogenates the Km of steroid sulfatase for DHEA sulfate increased from 15.4 in Tris buffer to 26.8 microM in phosphate (both buffers 0.1 M, pH 7.4), P less than 0.05. In 3 pooled ovarian preparations the Km increased from 14.3 microM in Tris to 33.0 microM in phosphate, P less than 0.01. There was no significant difference between the ovarian and placental values for Km in either Tris or phosphate (P greater than 0.5), and the increase in the Km produced by phosphate in ovarian tissue was not significantly different from that in the placenta (P greater than 0.5). In the placentas the Vmax in Tris was 1420 pmol/min/mg protein and this fell to 523 pmol/min/mg protein in phosphate (P less than 0.005). The Vmax was 50-fold higher in the placenta than in the ovary in either Tris or phosphate (both P less than 0.001). In the ovary, the Vmax was 27.6 pmol/min/mg protein in Tris and 11.0 pmol/min/mg protein in phosphate (P less than 0.05). The reduction of Vmax produced by phosphate in the ovary was not significantly different from that in the placenta (P greater than 0.5). The slope of the 1/v vs 1/S plot (Km/Vmax) increased 4.7-fold in the placentas and 5.8-fold in the ovaries in phosphate over that in Tris (both P less than 0.001); the increase in the placentas was not significantly different from that in the ovaries (P greater than 0.5). Phosphate ion acts as a mixed inhibitor of both placental and ovarian steroid sulfatase.

Arylsulfatases↗
PubMed1992

Multiple-marker screening in pregnancies with hydropic and nonhydropic Turner syndrome.

OBJECTIVE: The combination of maternal serum alpha-fetoprotein, unconjugated estriol, and human chorionic gonadotropin levels and maternal age has been used to increase the sensitivity of screening for fetal Down syndrome and trisomy 18 in early-second-trimester pregnancies. We hypothesized that a unique pattern of these analytes also may be characteristic of fetal Turner syndrome, with or without hydrops. STUDY DESIGN: We studied preamniocentesis, second-trimester maternal serum specimens from seven hydropic and eight nonhydropic cases of fetal Turner syndrome. Clinical and pathologic records were reviewed. Statistical analysis of the data was performed by the rank sum test. RESULTS: In both hydropic and nonhydropic cases, alpha-fetoprotein levels were slightly reduced, and unconjugated estriol levels were markedly reduced. In hydropic pregnancies human chorionic gonadotropin levels were elevated, and nonhydropic pregnancies had low human chorionic gonadotropin levels (p = 0.001). CONCLUSIONS: The results suggest that the morphologic defect of hydrops, rather than the aneuploidy itself, is responsible for the elevation in human chorionic gonadotropin. In conjunction with the low unconjugated estriol levels, the elevation in human chorionic gonadotropin levels will result in the prenatal identification of hydropic fetal Turner syndrome pregnancies as being at increased risk for fetal Down syndrome.

Biomarkers↗
PubMed1990

Steroid sulphatase activity in the human ovarian corpus luteum, stroma, and follicle: comparison to activity in other tissues and the placenta.

Steroid sulfatase activity was measured in 89 human samples, using dehydroepiandrosterone sulfate (DHEAS) as substrate. The lowest activity was that of follicular fluid which was significantly lower than that of other tissues tested (each P less than 0.01). The steroid sulfatase activity of ovarian tissue taken collectively (corpus luteum, stroma, and follicles) was higher than that of other tissues taken collectively (abdominal skin, uterus, and fallopian tube) (P less than 0.001), and the steroid sulfatase activity of either the follicle (P less than 0.01) or the stroma (P less than 0.05) was significantly greater than that of the corpus luteum. The geometric mean steroid sulfatase activity of the placenta was significantly higher than other tissues tested (each P less than 0.01) and was 22-fold higher than that of the follicle, the tissue with the next highest activity. These data indicate that the human ovary (particularly the stroma and follicle) is capable of utilizing DHEAS, an adrenal product, as a substrate for production of other androgens such as dehydroepiandrosterone (DHEA), androstenedione, and testosterone.

Arylsulfatases↗
PubMed1990

Maternal serum screening for aneuploid pregnancy by alpha-fetoprotein, hCG, and unconjugated estriol.

A number of serum screening protocols are either currently in use or proposed to identify pregnant women under 35 years of age who are at increased risk for a Down syndrome fetus. It has been suggested that these same screening methods be applied to gravidas over 35 years of age to identify those women who should be offered amniocentesis. To evaluate the efficacy of screening for detection of aneuploid pregnancy in this age group, the serum samples of 34 women who underwent amniocentesis and who had confirmed fetal aneuploidy were assayed for alpha-fetoprotein (AFP), hCG, and unconjugated estriol (E3). These concentrations were compared with those of 85 women with known euploid pregnancy who underwent amniocentesis for advanced maternal age. The mean multiple of the median (MoM) for each of the three markers was significantly different from control values in cases of trisomy 21 (AFP median MoM = 0.82; unconjugated E3 median MoM = 0.77; and hCG median MoM = 1.89). These differences were not found when other aneuploidies were considered. Likelihood ratios were calculated for cases and controls and examined for their ability to predict the need for amniocentesis, based on currently recommended risk levels. There was a significant difference between the mean likelihood ratio for cases of trisomy 21 compared with that of controls (mean likelihood ratio = 13.48); there was no significant difference for other aneuploidies (mean likelihood ratio = 1.08). Of the 16 cases of trisomy 21 analyzed, four would not have been diagnosed antenatally if recommendation against amniocentesis had been made based on each woman's individual age-specific risk as modified by her likelihood ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex Hormones↗
PubMed1979

Testicular aromatization in immature rats: localization and stimulation after gonadotropin administration in vivo.

Aromatization was measured in testicular microsomal preparations obtained from rats treated 3--4 days with FSH, hCG, or vehicle, hCG, but not FSH, was found consistently to stimulate testicular aromatase activity at least 10-fold. As a marker for FSH action, epididymal androgen-binding protein was assayed and found to be 3 times higher in FSH-treated rats than in either hCG or control rats. hCG, but not FSH or vehicle, stimulated serum testosterone levels more than 100-fold. In all groups, aromatase activity in the microsomal fraction was at least 6 times higher than that found in the mitochondrial fraction. In experiments in which testicular compartments were separated, microsomal preparations from interstitial tissue of hCG-treated rats had 5--7 times more aromatase activity than microsomes from seminiferous tubules and 2--3 times more activity than microsomes from whole testes. It is concluded the hCG administered in vivo can stimulate testicular aromatase activity in immature rats, and the increase in activity is localized in the interstitial tissue.

Animals↗
PubMed1978

Properties of the aromatase system associated with the mitochondrial fraction of human placenta.

The aromatase system associated with the mitochondrial fraction of human term placenta, present at 35--50% the specific activity of the microsomal enzyme, is substantially the same as the microsomal enzyme as determined by the following: 1) The rate of aromatization of androstenedione, 19-nortestosterone, and 16alpha-hydroxytestosterone in mitochondria was a nearly constant proportion of the microsomal rate; 2) Sensitivity to carbon monoxide was the same; 3) The magnitude of cytochrome P-450 Type I spectral interactions with androgen substrates was a constant proportion in mitochondria and microsomes; 4) Sensitivity to an antibody raised against hepatic microsomal NADPH-cytochrome c reductase was the same. When inner and outer mitochondrial membrane subfractions were prepared, the predominant aromatase activity was associated with the outer membrane preparation. This aromatase activity could not be accounted for by microsomal contamination as determined by inosine diphosphatase activity, a microsomal marker. After correction, the rate of aromatization in the outer membrane preparation was almost six times that in the inner membranes and three times that of the whole mitochondrial fraction.

Androstenedione↗
PubMed1978

Estrogen 2-hydroxylase: activity in rat tissues.

Incubation parameters for a radioderivative assay for estrogen 2-hydroxylase have been examined. The assay was found to be specific and sensitive if a chromatographically purified preparation of COMT was used. Estradiol was found to be a better substrate for the 2-hydroxylase than estrone or estriol. The liver had significantly higher estrogen 2-hydroxylase activity than any other tissue examined. The estrogen 2-hydroxylase was highly localized in the microsomal fraction in both the liver and the brain. The male rat was found to have significantly more estrogen 2-hydroxylase activity in the liver than the female rat. In addition, in the male rat liver, the estrogen 2-hydroxylase activity was reversibly inducible by testosterone and was not affected by phenobarbital. In the male and female rat brain the estrogen 2-hydroxylase activities were similar.

Animals↗
PubMed1977

The aromatization of androgens by primary monolayer cultures of fetal rat hypothalamus.

Aromatization of [3H]androstenedione and [3H]19-hydroxyandrostenedione to [3H]estrone has been demonstrated to occur in one to two week old primary monolayer cultures of fetal rat hypothalamus. Three times more estrone is produced from 19-hydroxyandrostenedione than from androstenedione in four day incubations. Cultures treated with cytosine arabinoside have 50% less cellular protein and produce three times more estrone from either substrate than untreated cultures. Time course experiments using cultures treated with cytosine arabinoside indicate that aromatization of 19-hydroxyandrostenedione is linear for three days and can be quantitatively measured within the first two to eight hours of incubation.

Androstenedione↗
PubMed1977

Danazol inhibits steroidogenesis in the rat testis in vitro.

The effects of danazol on steroidogenesis in vitro in the rat testis were examined by studying: 1) androgen synthesis in rat Leydig cells cultured with danazol, 2) danazol binding to rat testis microsomal cytochrome P-450, and 3) enzyme kinetics of danazol inhibition of the microsomal enzymes of testicular steroidogenesis. Concentrations of danazol as low as 1 micrometer suppressed LH-stimulated testosterone and androstenedione production in cultured Leydig cells. The addition of danazol to a preparation of testicular microsomes elicited a type I cytochrome P-450 binding spectrum, with an apparent spectral dissociation constant (Ks) of 4.8 micrometer. Danazol inhibited progesterone and 17alpha-hydroxy-progesterone binding to microsomal P-450 with apparent spectral inhibition constants of 2.4 micrometer and 2.8 micrometer, respectively. Danazol competitively inhibited 3beta-hydroxy-delta5-steroid dehydrogenase-isomerase (apparent enzymatic inhibition constant, KI = 5.8 micrometer), 17alpha-hydroxylase (KI = 2.4 micrometer), 17,20 lyase (KI = 1.9 micrometer), and 17beta-hydroxysteroid dehydrogenase (KI = 4.4 micrometer). These findings indicate that low concentrations of danazol directly inhibit steroidogenesis in the rat testis in vitro.

Androgens↗
PubMed1977

Danazol inhibits steroidogenesis.

Danazol was found to inhibit multiple enzymes of steroidogenesis directly in the pregnant mare serum (PMS)-treated hamster ovary and the rat testis and adrenal in vitro. In the PMS-treated hamster ovary, danazol inhibited 17alpha-hydroxylase, 17,20-lyase, and 3beta-hydroxysteroid dehydrogenase. In the rat testis, danazol inhibited 17alpha-hydroxylase, 17,20-lyase, 3beta-hydroxysteroid dehydrogenase, and 17beta-hydroxysteroid dehydrogenase. In the rat adrenal, danazol inhibited 3beta-hydroxysteroid dehydrogenase, 21-hydroxylase, and 11beta-hydroxylase. Two hours after a subcutaneous injection of 5 mg/kg of danazol to adult male rats, serum luteinizing hormone levels were significantly increased and serum testosterone levels were significantly suppressed. These findings suggest that in the rodent one of danazol's major pharmacologic effects is the direct inhibition of steroidogenesis.

Adrenal Glands↗
PubMed1976

Cytochrome P-450 and the aromatization of 16alpha-hydroxytestosterone and androstenedione by human placental microsomes.

When measured in vitro using human placental microsomal preparations, the aromatization of 16alpha-hydroxytestosterone to estriol and androstenedione to estrone and estradiol proceeds at almost identical initial rates. Important differences between 16alpha-hydroxytestosterone and adrostenedione aromatization are evident, however. While substantial findings have implicated cytochrome P-450 in placental aromatization, the aromatizaiton of androstenedione is insensitive to CO although it is competitively inhibited by metyrapone. 16alpha-Hydroxytestosterone aromatization, in contrast, is inhibited 50-60% by CO and is strongly inhibited by metyrapone. 16alpha-hydroxytestosterone aromatization is strongly inhibited in a competitive manner by androstenedione, while 16alpha-hydroxytestosterone has essentially no effect on androstenedione aromatization, althogh at very high 16alpha-hydroxytestosterone concentrations (65 muM) and subsaturating androstenedione concentrations, 16alpha-hydroxytestosterone appears to noncomptitively inhibit androstenedione aromatization. The apparent Km for the aromatization of androstenedione is 95 nM and for 16alpha-hydroxytestosterone, 7 muM. Both androstenedione and 16alpha-hydroxytestosterone cause type I spectral perturbations associated with binding to cytochrome P-450 when added to placental microsomes; however, the deltaA390-420 is twice as great in response to saturating amounts of androstenedione than in response to 16alpha-hydroxytestosterone. If androstenedione is added to 16alpha-hydroxytestosterone, the same spectral change as that caused by androstenedione alone is expressed. The apparent spectral dissociation constant for androstenedione is 93 nM while for 16alpha-hydroxytestosterone it is 11muM; both essentially the same as the comparable apparent Kms for aromatization. The evidence suggests the presence of two aromatase P-450's in human placenta.

Androstenedione↗