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Biomedical subjects

D Crook

Publications and source records attributed to D Crook.

At least 91 records · Page 5Linked to original sources
PubMed1992

Danazol induces resistance to both insulin and glucagon in young women.

1. Danazol elevates plasma insulin, plasma glucagon and serum low-density lipoprotein concentrations and reduces the serum high-density lipoprotein concentration. 2. Associations between these disturbances were studied in 17 women receiving danazol therapy for endometriosis. Eleven women underwent intravenous glucose tolerance tests with measurement of plasma glucose, insulin, C-peptide and glucagon concentrations and modelling analysis of intravenous glucose tolerance test concentration profiles. Six women underwent glucagon sensitivity tests. Serum concentrations of lipids and lipoproteins were measured in all cases. 3. Danazol reduced the fasting plasma glucose and insulin concentrations, but markedly raised the fasting plasma glucagon concentration. The insulin and C-peptide responses to the intravenous glucose tolerance test were increased twofold and the net decrement in glucagon concentration was increased tenfold. The glucose response to the intravenous glucose tolerance test was unaffected. Insulin sensitivity was reduced by 55%. Both first-phase plasma insulin responsiveness and net first-phase pancreatic insulin secretion were increased; insulin half-life was prolonged. The glucose response to the glucagon sensitivity test was reduced on treatment. The calculated low-density lipoprotein cholesterol level rose by 20%, whereas high-density lipoprotein cholesterol level fell by 47%. None of these changes in serum lipoprotein levels correlated with changes in insulin metabolism. In general, metabolic changes normalized after 3 months. 4. Danazol increases the sensitivity of pancreatic insulin and glucagon secretion to glucose. Danazol-induced insulin and glucagon resistance could be due to receptor down-regulation resulting from hypersecretion of insulin and glucagon.

Adult↗
PubMed1992

Influence of insulin resistance, secretion, and clearance on serum cholesterol, triglycerides, lipoprotein cholesterol, and blood pressure in healthy men.

Relations between serum lipids, lipoproteins, blood pressure, and insulin metabolism were investigated in 158 healthy men aged 19-77 years and with body mass indexes (BMIs) of 19-41 kg.m-2. Mathematical modeling analysis of glucose, insulin, and C-peptide concentrations during an intravenous glucose tolerance test was used to measure parameters of insulin metabolism. In univariate analysis, both fasting and postglucose insulin concentrations showed significant positive associations with fasting serum triglyceride levels (r = 0.33 and 0.38, respectively) and systolic (r = 0.22 and 0.26) and diastolic (r = 0.21 and 0.24) blood pressure and negative associations with high density lipoprotein subfraction 2 cholesterol (HDL2; r = -0.21 and -0.25). In multivariate analysis, the associations between insulin and HDL2 cholesterol concentrations were found to depend on triglyceride levels. Insulin resistance and basal pancreatic insulin secretion showed significant positive associations with serum triglycerides, which were independent of the effects of age, BMI, and fat distribution. Hepatic insulin throughout was independently associated with HDL2 cholesterol. Associations of insulin-related variables with blood pressure were generally dependent on age and BMI. These results underline the importance of insulin sensitivity and insulin concentrations as determinants of triglyceride metabolism. They also indicate a close relation between hepatic insulin handling and HDL2 concentration that is independent of triglyceride metabolism.

Adult↗
PubMed1992

Inverse relationship between serum Lp(a) levels and first-phase insulin secretion.

Relationships between serum Lp(a) levels and insulin metabolism were investigated in 147 healthy nonobese men attending an executive health-screening program. Each subject received an IVGTT with measurement of plasma levels of glucose, insulin, and C-peptide. An inverse relationship was seen with the first-phase plasma insulin response when subjects were stratified into quartile ranges of the serum Lp(a) distribution. This relationship was supported by mathematical modeling analyses of these data, which revealed an inverse relationship between serum Lp(a) levels and first-phase pancreatic insulin secretion and plasma insulin responsiveness to glucose.

Blood Glucose↗
PubMed1991

Pulsatility index in internal carotid artery in relation to transdermal oestradiol and time since menopause.

The protection afforded by postmenopausal oestrogen replacement against cardiovascular disease is not fully explained by changes in plasma lipoproteins. To investigate the effect of oestrogen on arterial tone, Doppler ultrasound was used to assess blood flow characteristics in the internal carotid arteries of 12 postmenopausal women. Patients were studied pretreatment and at weeks 4, 6, 9, and 22 of therapy with transdermal oestradiol 50 micrograms/day. The pulsatility index (PI), which is thought to represent impedance to blood flow distal to the point of sampling, was measured from the flow velocity waveform. 11 of the 12 patients were within 5 years of menopause; 1 was 8 years postmenopausal but had experienced bleeding 4 years after menopause. In the 11 women there was a highly significant correlation (r = 0.77) between time since menopause and baseline PI. A similar correlation (r = 0.74) was observed when the episode of postmenopausal bleeding was redefined as time of menopause in the twelfth patient. For all 12 patients, there was a significant negative correlation (r = -0.70) between change in PI during transdermal oestradiol therapy and mean of baseline plus week 22 PI value. For all correlations between changes in PI and time since menopause, the longer the time the greater the fall in PI. These results, and previous observations of a reduction in uterine artery PI with oestradiol treatment, suggest that oestrogen has a generalised effect on the arterial system.

Administration, Cutaneous↗
PubMed1991

Lipid and carbohydrate metabolism in premenopausal women given subdermal estradiol implants.

Fifteen premenopausal women were studied before and 6 weeks after receiving subcutaneous implants of 100 mg estradiol. Serum estradiol levels doubled; increases were also seen in fasting serum total cholesterol and in high-density lipoprotein cholesterol (HDL). This increase was confined to the HDL2 subfraction, and was not reflected in the HDL apolipoproteins. Low density lipoprotein (LDL) cholesterol levels were unchanged, as were those of apolipoprotein B, the major protein component of LDL. Carbohydrate metabolism was assessed in a subgroup of 12 women. Estrogen implantation reduced fasting plasma glucose levels but did not alter the plasma glucose response to an oral glucose tolerance test. Plasma insulin levels were unchanged both in the fasted state and during the glucose tolerance test. Our findings indicate that parenteral administration of estradiol can alter lipid and carbohydrate metabolism in premenopausal women.

Adult↗
PubMed1991

Oral contraceptives and metabolic risk markers for coronary heart disease.

Disturbances in both the plasma lipid profile and in insulin handling have been implicated in the development of coronary heart disease (CHD). Estrogens and progestins are known to affect significantly both lipid and insulin metabolism. Since an increased incidence of myocardial infarction has been identified among users of oral contraceptives (OCs), the metabolic effect of these drugs on risk factors for CHD is of interest. Comparison of a range of monophasic and triphasic OCs that differ primarily in their progestin content has shown that lowering the progestin dose and using a less androgenic steroid reduce the impact on both low-density lipoproteins and high-density lipoproteins (HDLs). In terms of the HDL-2 subfraction, a lipoprotein class that may be of special relevance to the development of CHD, low-dose norethindrone and desogestrel monophasic agents had the least adverse effect. Triglyceride levels were increased by the low-dose OCs used in this study; this may be an unavoidable consequence of current trends in OC development. However, the clinical significance of these increased triglyceride levels is not clear. Glucose tolerance deteriorated similarly with all the formulations in this study, although the effect on insulin concentrations was less marked with formulations containing lower doses of progestins. It was concluded that reducing the progestin dose and changing the progestin type effectively reduce the adverse impact of OCs on metabolic risk for CHD. Although further study is recommended, the use of OC formulations without adverse effects on risk profile is indicated.

Adolescent↗
PubMed1991

Coronary heart disease risk markers in users of low-dose oral contraceptives.

Seven combination oral contraceptives (OCs) were studied for their effects on glucose, insulin, triglyceride and lipoprotein concentrations. Subjects included 925 women using fixed-dose (monophasic) or variable-dose (triphasic) formulations and 418 premenopausal women not using OCs. The monophasics contained 150 or 250 micrograms of levonorgestrel, 500 or 1,000 micrograms of norethindrone or 150 micrograms of desogestrel as the progestin. Triphasic progestin doses were 50-125 micrograms of levonorgestrel or 500-1,000 micrograms of norethindrone. All the formulations increased the fasting serum triglycerides. No changes were seen in serum total cholesterol. The effects on serum lipoproteins depended on the progestin type and dose. Monophasics containing 500 micrograms of norethindrone or 150 micrograms of desogestrel lowered low density lipoprotein (LDL) cholesterol and increased high density lipoprotein (HDL) cholesterol. Monophasics containing levonorgestrel reduced HDL cholesterol. The triphasics did not affect LDL or HDL cholesterol but altered the balance of HDL subfractions. All the formulations caused a deterioration in glucose tolerance and insulin resistance and increased pancreatic insulin secretion. The greatest effects were seen with formulations containing levonorgestrel. The study showed that a reduction in the progestin dose and use of novel progestins can reduce the potentially adverse effects of OCs on metabolic risk markers for coronary heart disease.

Adolescent↗
PubMed1990

The effects of different formulations of oral contraceptive agents on lipid and carbohydrate metabolism.

BACKGROUND: Oral contraceptives can induce changes in lipid and carbohydrate metabolism similar to those associated with an increased risk of coronary heart disease, including increased serum triglyceride, low-density lipoprotein (LDL) cholesterol, and insulin levels and decreased high-density lipoprotein (HDL) cholesterol levels. In this study, we examined whether modification of the type or dose of progestin in oral-contraceptive preparations diminishes these changes. METHODS: We measured plasma lipoprotein levels and performed oral glucose-tolerance tests in a cross section of 1060 women who took one of nine types of oral contraceptives for at least three months and 418 women who took none. Seven of the contraceptive formulations contained various doses and types of progestin: levonorgestrel in low (150 micrograms), high (250 micrograms), and triphasic (50 to 125 micrograms) doses; norethindrone in low (500 micrograms), high (1000 micrograms), and triphasic (500 to 1000 micrograms) doses; and a new progestin, desogestrel, in one dose (150 micrograms). All seven contained 30 to 40 micrograms of ethinyl estradiol. Two additional formulations contained progestin alone. RESULTS: As compared with controls, women taking combination drugs did not have increased serum total cholesterol levels but did have increases of 13 to 75 percent in fasting triglyceride levels. Levels of LDL cholesterol were reduced by 14 percent in women taking the combination containing desogestrel and by 12 percent in those taking low-dose norethindrone. Levels of HDL cholesterol were lowered by 5 percent and 16 percent by the combinations containing low-dose and high-dose levonorgestrel, respectively; these decreases were due to reductions of 29 percent and 43 percent, respectively, in the levels of HDL subclass 2. The combination pill containing high-dose norethindrone did not affect HDL cholesterol levels, whereas that containing low-dose norethindrone increased HDL cholesterol levels by 10 percent. The desogestrel combination increased HDL cholesterol levels by 12 percent. Levels of apolipoproteins A-I, A-II, and B were generally increased by combination drugs. Depending on the dose and type of progestin, combination drugs were associated with plasma glucose levels on the glucose-tolerance test that were 43 to 61 percent higher than in controls, insulin responses 12 to 40 percent higher, and C-peptide responses 18 to 45 percent higher. Progestin-only formulations had only minor metabolic effects. CONCLUSIONS: The appropriate dose and type of progestin may reduce the adverse effects of oral contraceptives on many metabolic markers of risk for coronary heart disease. Progestin-only formulations or combinations containing desogestrel or low-dose norethindrone were associated wtih the most favorable profiles.

Adolescent↗
PubMed1990

Transdermal administration of oestrogen/progestagen hormone replacement therapy.

The effects of an oestrogen/progestagen transdermal therapeutic system (TTS) were evaluated in sixteen oestrogen-deficient women. The patients applied conventional oestradiol-TTS for 14 days, then two combined norethisterone acetate/oestradiol patches for a further 14 days. The treatment was repeated for five cycles. Ten patients then underwent metabolic studies. One patient had amenorrhoea, but the rest experienced regular withdrawal bleeding which was seldom heavy. Fourteen endometrial biopsy samples were taken during the fifth treatment cycle; none showed proliferative or hyperplastic features. The effects of transdermal norethisterone acetate on symptoms, lipid metabolism, and psychological status were determined by comparing features in the oestrogen-only phase and in the combined phase; the effects were very mild. These preliminary findings show that transdermal progestagen can be successfully administered in hormone replacement therapy to prevent endometrial proliferation while minimising the adverse effects that may be seen with oral administration.

Administration, Cutaneous↗
PubMed1990

Hypertriglyceridemia and hypoxemia in small-for-gestational-age fetuses.

Plasma triglyceride concentration and blood oxygen tension were measured in samples obtained by cordocentesis from 35 small- and 54 appropriate-for-gestational-age fetuses at 18 to 36 weeks' gestation. In the appropriate-for-gestational-age fetuses there was an exponential decrease in plasma triglycerides with gestation. Some small-for-gestational age fetuses were hypertriglyceridemic and the degree of this biochemical disturbance was significantly correlated with the degree of fetal hypoxemia.

Adipose Tissue↗
PubMed1990

Low-dose oral contraceptives and carbohydrate metabolism.

Combined oral contraceptive use has been associated with increased incidence of impaired and diabetic glucose tolerance. Although increased risk of overt symptoms of diabetes has not been associated with oral contraceptive use, increased risk of coronary heart disease has been consistently demonstrated. Diabetes is associated with increased risk of coronary heart disease, especially in women. Elevated plasma glucose and insulin concentrations are also associated with increased risk of coronary heart disease. Studies of the effects of low-dose oral contraceptives on glucose tolerance test plasma glucose and insulin levels are reviewed. Low-dose combined oral contraceptives induced changes in measures of carbohydrate metabolism in directions consistent with increased risk of coronary heart disease. The magnitude of these changes may depend on the dose and type of progestogen. The clinical implications of these changes are unknown, but it would seem advisable to minimize them where possible.

Blood Glucose↗
PubMed1990

Endocrine control of plasma lipoprotein metabolism: effects of gonadal steroids.

Gonadal steroids are powerful modulators of plasma lipoprotein metabolism. In general, steroids with oestrogenic activity increase plasma levels of HDL, especially HDL2, and reduce levels of LDL. Steroids with androgenic activity have opposite effects, consistent with the sex difference in HDL and LDL levels. Triglyceride levels are lowered by exogenous administration of androgens and are raised by oral oestrogens, contrary to the observed sex difference in this lipid. The impact of administered gonadal steroids is modified by factors such as dosage and chemical structure, with synthetic steroids having a more pronounced effect than natural hormones. The effects of these steroids may depend on the pre-treatment lipoprotein pattern and endocrine status, and are modified by the route of administration, with oral hormones often having greater metabolic effects than those given parenterally. The net effects of oestrogen and progestagen combined preparations on lipoprotein metabolism depends on the balance between oestrogenic and androgenic activity. In contrast, endogenous changes in sex hormone levels, such as those accompanying puberty, the menstrual cycle and the menopause, have relatively little effect on plasma lipoproteins. Data concerning puberty and castration in males indicate that testosterone is a key factor in the sex difference in HDL levels. There is evidence that loss of ovarian function induces significant increases in LDL level, but endogenous changes in oestrogen levels have little effect on HDL metabolism in women. Changes in triglyceride levels are due mainly to alteration in VLDL secretion and catabolism. LDL levels are controlled by the activity of B100, E receptors and, to a lesser extent, changes in LCAT activity. Gonadal steroids affect HDL levels by altering apoAI synthesis and by controlling the activity of hepatic lipase. Lp(a) levels are increased during early pregnancy but may be decreased by anabolic steroids. The mechanisms behind such actions are unknown. Gonadal hormones influence all areas of plasma lipoprotein metabolism and therefore may affect cardiovascular risk by favourably affecting the plasma lipoprotein profile. In postmenopausal women, use of oestrogens has led to a 60% reduction in cardiovascular disease (Bush et al, 1987). Androgens and progestagens with androgenic properties induce changes in plasma lipoproteins which may increase risk. Further study of the mechanisms involved in these changes is obligatory given the widespread use of these hormones.

Androgens↗
PubMed1990

The role and use of progestogens.

Certain epidemiologic, histologic, and biochemical data on the effects of estrogens and progestogens on the endometrial, physical, psychological, and lipid status of postmenopausal women are reviewed. Unopposed estrogen replacement increases the risk of endometrial cancer not only while treatment is being taken but also for many years after it is discontinued. Strategies must be developed for posttreatment surveillance. The addition of a cyclic progestogen reduces this risk, but it is not clear whether the reduction is to, or below, that observed in an untreated population. Protective doses of C-19 (norethindrone) and C-21 (medroxy-progesterone acetate) progestogens are suggested. All progestogens may cause physical, psychological, and metabolic side effects. In addition, most women taking cyclic progestogens experience regular withdrawal bleeding. Continuous/combined therapy has been introduced to minimize these side effects and induce amenorrhea. Published data on the efficacy and safety of continuous combined therapy are few. Although the regimen is effective in relieving menopausal symptoms and inducing endometrial atrophy in most patients, side effects of progestogen are common and there is a high incidence of bleeding in the first few months, which is unacceptable to many patients. In our view, the effect of continuous combined therapy on lipids and lipoproteins has not been properly addressed. Based upon the available literature, we believe that the enthusiasm for continuous combined therapy is premature and we urge caution in its use until further, more conclusive, data become available.

Drug Administration Schedule↗
PubMed1989

Plasma lipoprotein lipids in relation to the MspI polymorphism of the apolipoprotein AII gene in Caucasian men. Lack of association with plasma triglyceride concentration.

Digestion of the human apolipoprotein (apo) A-II gene with the endonuclease MspI produces fragments of 3.0 or 3.7 kb, reflecting the presence or absence of a polymorphic site within an Alu sequence 3' to the gene. Patients with hypertriglyceridemia have been shown to have an increased prevalence of the 3.0 kb allele. To explore this observation further, plasma lipoprotein lipids were studied in a random sample of fasted middle-aged Caucasian men, of which 59 were 3.0 kb homozygotes, 24 were heterozygotes, and 2 were 3.7 kb homozygotes. After adjusting for the effects of age, height, weight, alcohol intake and cigarette consumption by covariance analysis, no statistically significant associations were present between genotype and the concentrations of triglyceride in whole plasma or the d less than 1.019 g/ml fraction of plasma (i.e., VLDL + IDL). Nor were the cholesterol concentrations in VLDL + IDL, low density lipoprotein (LDL, d = 1.019-1.063 g/ml), high density lipoprotein (HDL), HDL2 or HDL3 related to genotype. In an independent comparison of eight 3.0 kb homozygotes and eight 3.7 kb homozygotes (all Caucasians) drawn from a different community, genotype was unrelated to the triglyceride or cholesterol concentrations in VLDL (d less than 1.006 g/ml), IDL + LDL (d = 1.006-1.063 g/ml) or HDL, after adjustment for the effects of covariates. These results suggest that the MspI polymorphism of the apo A-II gene is not associated with genetic variation that significantly affects triglyceride transport in the majority of men.(ABSTRACT TRUNCATED AT 250 WORDS)

Apolipoprotein A-II↗