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Biomedical subjects

G S Tint

Publications and source records attributed to G S Tint.

At least 73 records · Page 4Linked to original sources
PubMed1997

Increased bile acid pool inhibits cholesterol 7 alpha-hydroxylase in cholesterol-fed rabbits.

BACKGROUND & AIMS: Cholesterol feeding unexpectedly inhibits cholesterol 7 alpha-hydroxylase in rabbits. The aim of this study was to explore the mechanism. METHODS: Twenty male New Zealand white rabbits were fed regular chow with and without 2% cholesterol for 10 days followed by 7 days of bile drainage. The activities of hepatic cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase that control bile acid synthesis in classic and alternative pathways were related to the size and composition of bile acid pool. RESULTS: After feeding cholesterol, plasma and hepatic cholesterol concentrations increased, the bile acid pool doubled (from 254 +/- 44 to 533 +/- 51 mg; P < 0.001), cholesterol 7 alpha-hydroxylase activity decreased 68% (P < 0.01), but sterol 27-hydroxylase activity increased 66% (P < 0.05) with increased cholic acid synthesis (P < 0.01). Bile drainage in the cholesterol-fed rabbits depleted the bile acid pool and stimulated down-regulated cholesterol 7 alpha-hydroxylase activity 11.4-fold (P < 0.001), although hepatic cholesterol remained elevated. Hepatic sterol 27-hydroxylase activity was unaffected. CONCLUSIONS: Feeding cholesterol increased hepatic cholesterol and stimulated sterol 27-hydroxylase and alternative bile acid synthesis, which expanded the bile acid pool and inhibited cholesterol 7 alpha-hydroxylase in rabbits. In distinction, hepatic sterol 27-hydroxylase was insensitive to changes in the bile acid pool.

Animals↗
PubMed1997

Rapid identification of Smith-Lemli-Opitz syndrome homozygotes and heterozygotes (carriers) by measurement of deficient 7-dehydrocholesterol-delta 7-reductase activity in fibroblasts.

To extend the enzyme deficiency in Smith-Lemli-Opitz syndrome (SLOS) to extrahepatic tissues, 7-dehydrocholesterol-delta 7-reductase activity was measured in fibroblasts from 10 controls, five SLOS homozygotes, and five obligate heterozygotes. In cells grown almost to confluence in cholesterol-containing medium (4 mg/dL), the conversion of [1,2-3H]7-dehydrocholesterol to cholesterol (7-dehydrocholesterol-delta 7-reductase activity) was 3.8 times higher in control than in homozygote cells and 2.2 times higher than in heterozygote cells. After 24 hours' exposure of the fibroblasts to cholesterol-deficient medium supplemented with lovastatin, 7-dehydrocholesterol-delta 7-reductase activity increased twofold in controls, but did not change significantly in either heterozygous or homozygous cells. In contrast, the activities of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and lathosterol 5-dehydrogenase, two key enzymes that precede 7-dehydrocholesterol-delta 7-reductase in the cholesterol biosynthetic pathway, and low-density lipoprotein (LDL) receptor-mediated binding were equal in control, homozygote, and heterozygote fibroblasts. Further, HMG-CoA reductase activity and LDL receptor-mediated binding increased after exposure of the cells to cholesterol-deficient medium. Fibroblast cholesterol concentrations were approximately equal, although homozygote cells contained 30 times more 7-dehydrocholesterol. Thus, markedly reduced 7-dehydrocholesterol-delta 7-reductase activity that cannot be upregulated after exposure of the cells to cholesterol-deficient medium is diagnostic for the biochemical defect in SLOS. Significantly reduced enzyme activity between the levels in controls and homozygotes without accumulation of 7-dehydrocholesterol in fibroblasts identified heterozygotes.

Fibroblasts↗
PubMed1997

Synthesis of [3 alpha-3H]7-dehydrocholesterol via stable tritiated 4-phenyl-1,2,4-triazoline-3,5-dione derivative.

Synthesis of [3 alpha-3H]7-dehydrocholesterol is described via protection of the 5,7-diene system in 7-dehydrocholesterol as the Diels-Alder adduct with 4-phenyl-1,2,4-triazoline-3,5-dione followed by oxidation of the hydroxyl group to give the 3-oxo adduct. Reduction of the keto adduct with [3H]sodium borohydride produced the adduct of [3 alpha-3H]7-dehydrocholesterol from which the radiolabeled sterol was obtained via treatment with lithium aluminum hydride. The advantage of the method is that highly labeled [3 alpha-3H]7-dehydrocholesterol can be prepared. Further, unlike 7-dehydrocholesterol, its adduct with 4-phenyl-1,2,4-triazoline-3,5-dione is stable and can be stored. This allows the preparation of small batches of [3 alpha-3H]7-dehydrocholesterol for immediate use in biological experiments, and losses due to decomposition of excess radiolabeled 7-dehydrocholesterol are minimized.

Aluminum Compounds↗
PubMed1997

Comparative effect of dietary sitosterol on plasma sterols and cholesterol and bile acid synthesis in a sitosterolemic homozygote and heterozygote subject.

OBJECTIVE: Sitosterolemia is a genetic disorder characterized by an increased plasma plant sterol concentration due to enhanced sterol absorption coupled with reduced steroid excretion. The purpose of the present investigation was two-fold; first to assess the effects of a "basal" low sitosterol metabolic diet on plasma sterols and sterol balance, and, secondly, to quantify the relative influence of graduated increase in dietary sitosterol intake on a metabolic diet in a sitosterolemic homozygote, obligate heterozygote, and controls. METHODS: Patients were studied under strict metabolic conditions and fed a "basal" 30% fat, low-sitosterol (33 mg per 2000 kcal) diet. The level of dietary sitosterol was increased by addition of oils and resulted in final dietary sitosterol intakes of 1.8 mg/kg, 2.6 mg/kg and 3.5 mg/kg/day intakes of dietary sitosterol in the homozygote. These sitosterol dosages were selected based on sitosterol intakes equivalent to 2.6 mg/kg/day in the average American diet. Plasma cholesterol, sitosterol, and apolipoprotein A were measured, and stool collections assayed for sterol balance. RESULTS: Fecal sterol excretion and cholesterol synthesis were depressed markedly by 50% in the homozygote compared to the heterozygous parent, whereas plasma sitosterol levels were increased over 50-fold. When the sitosterol content of the diet was increased three-fold and dietary cholesterol was maintained in the homozygous and hypercholesterolemic control, plasma levels did not increase in the homozygote. Plasma cholesterol and sitosterol levels were unaffected in the hypercholesterolemic control. CONCLUSIONS: Plasma sterol levels remained elevated with the dietary sitosterol changes in the sitosterolemic homozygote. These findings were associated with a low fecal sterol excretion rate and depressed endogenous cholesterol synthesis. In this sitosterolemic patient, a very low sitosterol diet to curtail sterol input was of minimal therapeutic benefit. These results have important implications regarding the selection of therapy for this patient under these experimental conditions, but cannot be generalized to other homozygotes.

Adolescent↗
PubMed1996

Regulation of the last two enzymatic reactions in cholesterol biosynthesis in rats: effects of BM 15.766, cholesterol, cholic acid, lovastatin, and their combinations.

The Smith-Lemli-Opitz syndrome is a common inherited birth disorder caused by markedly reduced 7-dehydrocholesterol delta 7-reductase activity, the final enzyme in the cholesterol biosynthetic pathway. BM 15.766 (4-[2-[1-(4-chlorocinnamyl)piperazin-4-yl]ethyl]-benzoic acid) inhibits 7-dehydrocholesterol delta 7-reductase activity, reduces plasma cholesterol levels, and increases 7-dehydrocholesterol levels to reproduce the biochemical abnormalities of the syndrome in rats. Cholesterol, cholic acid, and lovastatin, alone or in combinations, were fed to rats given BM 15.766, and hepatic activities of the last two enzymes in the cholesterol biosynthetic pathway, lathosterol 5-dehydrogenase and 7-dehydrocholesterol delta 7-reductase, were measured. After feeding BM 15.766, hepatic 7-dehydrocholesterol delta 7-reductase activity decreased by 77% while lathosterol 5-dehydrogenase activity tended to increase, so that the ratio of 5-dehydrogenase to delta 7-reductase activities increased from 0.33 to 2.8. In BM 15.766-fed rats, treatment with cholesterol suppressed both 5-dehydrogenase and delta 7-reductase activities by 76% and 66%, respectively, and decreased the 5-dehydrogenase: delta 7-reductase activities ratio from 2.8 to 2.2. In contrast, treatment with cholic acid and BM 15.766 further inhibited delta 7-reductase activity by 67% without changing significantly the 5-dehydrogenase activity that had increased the ratio to 5.5. Combining BM 15.766 with lovastatin increased 5-dehydrogenase activity fivefold but did not change delta 7-reductase activity, raising the ratio to 14.3. In BM 15.766-treated rats, the first and last two enzymatic reactions in the cholesterol biosynthetic pathway catalyzed by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, lathosterol 5-dehydrogenase, and 7-dehydrocholesterol delta 7-reductase are down-regulated by cholesterol. Thus, only cholesterol and not cholic acid or lovastatin could reduce elevated plasma 7-dehydrocholesterol levels induced by BM 15.766.

Animals↗
PubMed1996

Blocking late cholesterol biosynthesis inhibits the growth of transplanted Morris hepatomas (7288CTC) in rats.

The conversion of 7-dehydrocholesterol to cholesterol is the last reaction in the cholesterol biosynthesis pathway catalyzed by the microsomal enzyme, 7-dehydrocholesterol-delta 7-reductase. We studied whether malignant tumor growth that depends on cholesterol could be slowed by inhibiting late cholesterol biosynthesis. The inhibitor 7-dehydrocholester-delta 7-reductase, BM 15.766 alone, or in combination with 2% cholesterol was fed to 20 male Buffalo rats for 2 weeks immediately after Morris hepatoma 7288CTC was implanted in both flanks. Tumor weights were compared and sterol composition, hepatic hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase activity, and low-density lipoprotein (LDL) receptor binding in the tumor were correlated with those in the liver. In the plasma of rats treated with BM 15.766, cholesterol levels dropped 75% and the precursor, 7-dehydrocholesterol rose substantially. Tumor weights were 43% less (P < .05) than controls (5.9 +/- 1.5 g vs. 10.4 +/- 2.2 g) with sterol concentrations reduced 25%, and the precursor, 7-dehydrocholesterol, increased to represent 71% of the tumor sterols. Feeding cholesterol with BM 15.766 normalized plasma but only partially restored tumor cholesterol concentrations, which still remained 49% below the hepatomas in the control group. With BM 15.766, hepatic cholesterol decreased 76% and was associated with a marked rise of 7-dehydrocholesterol that could be almost entirely prevented by feeding cholesterol. After the tumor was implanted, hepatic HMG-CoA reductase activity increased 56% and was 8.6 times higher than in the tumor. Enzyme activities were enhanced about 50% in the liver and the tumor after BM 15.766 was administered but decreased 38% below control when cholesterol was added to the diet. Hepatic receptor-mediated LDL binding rose 67% after tumor implantation, and declined to control levels with cholesterol feeding. These results suggest that de novo cholesterol synthesis in Morris hepatoma 7288CTC is much lower than the liver and tumor growth depends on circulating plasma cholesterol. Inhibiting the last step in cholesterol biosynthesis profoundly reduced tissue and plasma cholesterol concentrations and accumulated precursors substantially to slow hepatoma growth. Feeding cholesterol restored liver but not hepatoma cholesterol levels. Thus, inhibiting late cholesterol synthesis hinders growth of rapidly enlarging malignant tumors.

Animals↗
PubMed1996

Increasing hepatic cholesterol 7alpha-hydroxylase reduces plasma cholesterol concentrations in normocholesterolemic and hypercholesterolemic rabbits.

The effect of bile acid depletion and replacement with glycodeoxycholic acid on plasma cholesterol concentrations, hepatic low-density lipoprotein (LDL) receptor binding and messenger RNA (mRNA) levels, and hepatic activities and mRNA levels for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and cholesterol 7alpha-hydroxylase was investigated in 19 New Zealand white (NZW) and 15 Watanabe heritable hyperlipidemic (WHHL) rabbits. Bile acid depletion was produced by external bile drainage for 5 days, which maximized cholic acid synthesis. Replacement was achieved by infusing glycodeoxycholic acid intraduodenally for 24 hours so that the hepatic bile acid flux reached prefistula levels. Plasma and liver cholesterol concentrations were 13 times and 50% greater, respectively, hepatic LDL receptor-mediated binding was 26% less, and cholesterol 7alpha-hydroxylase activity and mRNA levels were 62% and 86% less in WHHL than NZW rabbits. After bile drainage, plasma cholesterol concentrations decreased 29% in NZW rabbits and 40% in WHHL rabbits and were associated with a 2.1-fold increase in hepatic LDL receptor-mediated binding in the NZW rabbits, but there was no change in the WHHL rabbits. Cholesterol 7alpha-hydroxylase activity and mRNA levels increased three and four times in NZW and WHHL rabbits, respectively, although liver cholesterol levels remained unchanged. Replacement with exogenous glycodeoxycholic acid increased plasma cholesterol concentrations 1.7 times in NZW rabbits and decreased enhanced cholesterol 7alpha-hydroxylase activity 54%, mRNA levels 86%, cholic acid synthesis 38%, and hepatic LDL receptor-mediated binding 57% in NZW rabbits. Bile acid depletion stimulated cholic acid synthesis by up-regulating cholesterol 7alpha-hydroxylase to use cholesterol and reduce plasma concentrations substantially in both NZW and WHHL rabbits, although LDL receptors did not function in WHHL rabbits. Glycodeoxycholic acid replacement inhibited elevated cholesterol 7alpha-hydroxylase, cholic acid synthesis, and hepatic LDL receptor binding to reestablish baseline plasma cholesterol levels in NZW rabbits. Hypercholesterolemia in WHHL rabbits was related to the combination of dysfunctional LDL receptors and inhibited cholesterol 7alpha-hydroxylase. Plasma cholesterol concentrations were reduced significantly when cholesterol 7alpha-hydroxylase was stimulated even in the absence of LDL receptor function.

Animals↗
PubMed1996

Abnormal cholesterol biosynthesis in sitosterolaemia and the Smith-Lemli-Opitz syndrome.

We investigated the enzyme defects in two inherited disorders of cholesterol biosynthesis: sitosterolaemia and the Smith-Lemli-Opitz syndrome. In sitosterolaemic homozygotes, plasma plant sterols (sitosterol and campesterol) concentrations are elevated because of enhanced intestinal absorption and diminished removal. Underlying these changes is very low cholesterol biosynthesis to provide extra sterol for cell growth. Extremely reduced activities of HMG-CoA reductase, the rate-controlling enzyme for cholesterol biosynthesis, caused by deficient HMG-CoA reductase mRNA is responsible and is the suspected inherited abnormality. The Smith-Lemli-Opitz syndrome is caused by a block in the last reaction in the cholesterol biosynthetic pathway, the conversion of 7-dehydrocholesterol to cholesterol, which is catalysed by 7-dehydrocholesterol delta 7-reductase. As a result, low plasma and tissue cholesterol with high 7-dehydrocholesterol levels are found in homozygotes, who show characteristic phenotypes of mental retardation, facial dysmorphism, and organ and limb congenital anomalies. Similar biochemical findings are produced in rats fed BM 15,766, an inhibitor of 7-dehydrocholesterol delta 7-reductase. Interestingly, feeding cholesterol can suppress abnormal cholesterol biosynthesis and improve symptoms in homozygotes and rats fed BM 15,766.

Animals↗
PubMed1996

Sitosterolemia: opposing effects of cholestyramine and lovastatin on plasma sterol levels in a homozygous girl and her heterozygous father.

Sitosterolemia is a genetic disorder characterized by sitosterol accumulation in plasma and clinically accelerated atherosclerosis. Under a condition of metabolic control with a 30% fat, low-sitosterol diet, we compared the effects of monotherapy and dual-drug treatment with lovastatin and cholestyramine on plasma sterol parameters and endogenous cholesterol synthesis in a homozygous sitosterolemic patient with concomitant heterozygous familial hypercholesterolemia (FH), her obligate heterozygous father, and hyperlipidemic control subjects. We found that for both the sitosterolemic homozygote and heterozygote, cholestyramine plus lovastatin dual therapy proved not to be superior to either drug treatment alone. In the homozygous patient, cholestyramine accounted for the decrease of plasma sterol (ie, lovastatin was ineffective), whereas in the heterozygote, lovastatin represented the margin of difference (ie, low-dose cholestyramine was relatively ineffective). Thus, the best treatment option for this homozygote child and her heterozygote father appears to be monotherapy with cholestyramine and lovastatin, respectively. Stimulation by bile acid malabsorption produced a dramatic decrease of plasma sterols in the homozygote, without increasing endogenous cholesterol synthesis, but this therapy was ineffective in the heterozygote. Decreasing endogenous cholesterol synthesis with lovastatin was effective in the heterozygote, but ineffective in the homozygote. In suspected sitosterolemia, a poor sterol response to lovastatin and a dramatic response to cholestyramine may differentiate homozygous from heterozygous and other familial forms of hyperlipidemia.

Adult↗
PubMed1996

Effect of YM 9429, a potent teratogen, on cholesterol biosynthesis in cultured cells and rat liver microsomes.

YM 9429 (cis-1-[4-(p-menthan-8-yloxy)phenyl]piperidine) is a hypolipidemic agent with a potent and specific teratogenicity, inducing cleft palate and skeletal variations in rats. Since cleft palate is generally observed in the Smith-Lemli-Opitz syndrome, a common syndrome of multiple congenital anomalies caused by reduced activity of 7-dehydrocholesterol delta 7-reductase (3 beta-hydroxysteroid delta 7-reductase), the final enzyme in the cholesterol biosynthetic pathway, YM 9429 was suspected of being an inhibitor of this enzyme. To prove this hypothesis, YM 9429 was added to cultured human skin fibroblasts and to cultured Morris hepatoma cells and incubated with [5-3H]mevalonolactone. After 24 h, radiolabeled 7-dehydrocholesterol accumulated in the cells, whereas the formation of radiolabeled cholesterol was markedly reduced. The results indicate that YM 9429 inhibits the conversion of 7-dehydrocholesterol to cholesterol catalyzed by the microsomal enzyme 7-dehydrocholesterol delta 7-reductase. In rat liver microsomes, the mode of inhibition was found to be noncompetitive, with a Ki of 40 microM. These results suggest that YM 9429 induced developmental abnormalities in rats by the same mechanism as the Smith-Lemli-Opitz syndrome. This compound might be useful for studying the pathogenesis of anomalies in animal models of the Smith-Lemli-Opitz syndrome.

Animals↗
PubMed1996

Abnormal cholesterol biosynthesis in the Smith-Lemli-Opitz syndrome.

The Smith-Lemli-Opitz syndrome is caused by an inherited defect in 7-dehydrocholesterol-delta7-reductase, the enzyme that catalyzes the last reaction in cholesterol biosynthesis, the conversion of 7-dehydrocholesterol to cholesterol. As a result, deficient cholesterol is produced and the precursor 7-dehydrocholesterol and derivatives (8-dehydrocholesterol and 19-nor-5,7,9(10)-cholestatrien-3 beta-ol) accumulate. Tissues (especially brain) deprived of cholesterol, or because of the deposited sterol precursors and derivatives, develop abnormally and function poorly. Replacement with dietary cholesterol may help correct the biochemical defects and improve symptoms.

Adolescent↗
PubMed1996

Measurement of 3 beta-hydroxysteroid delta 7-reductase activity in cultured skin fibroblasts utilizing ergosterol as a substrate: a new method for the diagnosis of the Smith-Lemli-Opitz syndrome.

A new sensitive and specific method for the evaluation of 3 beta-hydroxysteroid delta 7-reductase activity, the defective enzyme in the Smith-Lemli-Opitz (SLO) syndrome, is described. The assay is based on the use of gas chromatography-mass spectrometry with selected-ion monitoring to measure the mass of brassicasterol (ergosta-5,22-dien-3 beta-ol) produced by the incubation of ergosterol (ergosta-5,7,22-trien-3 beta-ol) with cultured human skin fibroblasts. Although the conversion of ergosterol to brassicasterol was slower than the transformation of [3H]7-dehydrocholesterol to [3H] cholesterol, cells from control subjects produced brassicasterol efficiently. In contrast, cells form SLO patients produced very little brassicasterol (P < 0.0001, patients vs. parents or vs. controls). These results indicate that the reduction of ergosterol can be used as an assay for 3 beta-hydroxysteroid delta 7-reductase in human skin fibroblasts, which avoids the many problems caused by the instability and lack of availability of radiolabeled 7-dehydrocholesterol. The present method made it possible to diagnose the SLO syndrome with high sensitivity and reliability using a commercially available compound.

Cholestadienols↗
PubMed1995

Capillary gas-liquid chromatography of 6-hydroxylated bile acids.

Gas-liquid chromatographic separation of several bile acids with a hydroxyl group at C-6 is described on two capillary columns, CP-Sil-19 CB and CP-Sil-5 CB. The gas-liquid chromatographic retention indices of bile acids with 6 alpha- and 6 beta-hydroxyl groups are compared with those of bile acids without the C-6 hydroxyl group and the effect of the C-6 hydroxyl group on the retention indices of bile acids is determined. Both 6 alpha- and 6 beta-hydroxyl groups increase the retention index of a bile acid. The retention indices of 6 alpha- or 6 beta-hydroxyl derivatives of chenodeoxycholic acid were found to be higher than those of the corresponding 6-hydroxy derivatives of cholic acid on the CP-Sil-19 CB column but lower on the CP-Sil-5 CB column. Although all 6-hydroxylated derivatives of lithocholic, chenodeoxycholic and cholic acids were not completely resolved on either column alone, combining the two columns resulted in the complete separation of all these compounds.

Bile Acids and Salts↗
PubMed1995

Unusual case of Smith-Lemli-Opitz syndrome "type II".

We describe a fetus with abnormalities suggestive, but not typical, of severe Smith-Lemli-Opitz syndrome (SLO). Biochemical studies demonstrated that there was a defect of cholesterol biosynthesis similar to that recently discovered in children with SLO. The findings in this fetus extend even further the wide spectrum of abnormalities of the SLO phenotype, and emphasize that a genetic pathological examination and biochemical studies should always be undertaken on atypical cases, especially fetuses.

Abnormalities, Multiple↗
PubMed1995

Severe Smith-Lemli-Opitz syndrome with prolonged survival and lipid abnormalities.

We have studied a girl with multiple congenital anomalies, growth and mental deficiency, characteristic facial anomalies, cataracts, cerebellar atrophy, and severe hypocholesterolemia. Death occurred at age 7 years. After excluding several syndromes, i.e., peroxisomal disorders, mevalonic acidaemia, and Marinesco-Sjögren syndrome, it is concluded that this girl had severe Smith-Lemli-Opitz Syndrome (SLOS) with exceptionally long survival. This diagnosis was confirmed through assay of 7-dehydrocholesterol in cultured fibroblasts.

Abnormalities, Multiple↗
PubMed1995

Prenatal detection of the cholesterol biosynthetic defect in the Smith-Lemli-Opitz syndrome by the analysis of amniotic fluid sterols.

The Smith-Lemli-Opitz (SLO or RSH) syndrome is an autosomal recessive disorder characterized by a recognizable pattern of minor facial anomalies, congenital anomalies of many organs, failure to thrive, and mental retardation. Its cause is a defect in cholesterol biosynthesis characterized by abnormally low plasma cholesterol levels and concentrations of the cholesterol precursor 7-dehydrocholesterol (7DHC) elevated up to several thousand-fold above normal. We used capillary column gas-chromatography to quantify sterols in amniotic fluid, amniotic cells, plasma, placenta, and breast milk from a heterozygous mother who had previously given birth to an affected son and in cord blood and plasma from her affected newborn daughter. The cholesterol concentration in amniotic fluid at 16 weeks gestation was normal, but 7DHC, normally undetectable, was greatly elevated. In cultured amniocytes, the level of 7DHC was 11% of total cholesterol, similar to cultured fibroblasts from patients with SLO syndrome. At 38 weeks, a girl with phenotype consistent with the syndrome was born. Cholesterol concentrations were abnormally low in cord blood and in the baby's plasma at 12 weeks, while levels of 7DHC were grossly elevated, confirming the prenatal diagnosis. The mother's plasma cholesterol increased steadily during gestation but remained below the lower 95% limit reported for normal control women. We conclude that it is now possible to detect the SLO syndrome at 16 weeks gestation by analyzing amniotic fluid sterols.

Amniotic Fluid↗