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Insulin resistance occurs in pre-eclampsia, but the cause is unknown. Furthermore, it is uncertain whether women destined to develop pre-eclampsia have a pre-existing insulin resistance or whether it is acquired with the development of the disease. We carried out this study to test the hypotheses that the increase in insulin resistance associated with pre-eclampsia is related to higher levels of tumor necrosis factor (TNF)-alpha, and that the increase in insulin resistance precedes the clinical onset of the disease. Fasting plasma samples were obtained from ten women who subsequently developed pre-eclampsia and ten normal pregnant controls at 16, 20, 24, 28, 32 and 36 weeks' gestation to measure circulating levels of insulin, glucose and TNF-alpha. Fasting insulin resistance index (FIRI) was calculated from insulin and glucose concentrations. In the normal controls, fasting insulin and TNF-alpha levels, and FIRI increased with gestation, and these were significantly greater than baseline values from 24, 28 and 28 weeks, respectively. In the group of women who developed pre-eclampsia, plasma levels of insulin and the FIRI were significantly higher than baseline from 20 and 24 weeks, respectively, but both were significantly higher than in the control group at 32 and 36 weeks. The increase in TNF-alpha in the pre-eclampsia group was significantly greater than in normal pregnant controls (p < 0.001). However, there was no significant association between TNF-alpha levels and FIRI in either normal pregnancy or pregnancies developing pre-eclampsia. These data suggest that insulin resistance in pre-eclampsia precedes the clinical onset of the disease, but that it is not related to elevated levels of TNF-alpha.

It is desirable that young women with primary ovarian failure achieve normal peak bone mass to reduce the subsequent risk of osteoporosis, and that there are management strategies to replace bone that is already lost. While estrogen (E2) is generally considered to prevent bone loss by suppressing bone resorption, it is now recognized that estrogen also exerts an anabolic effect on the human skeleton. In this study, we tested whether estrogen could increase bone mass in women with primary ovarian failure. We studied the mechanism underlying this by analyzing biochemical markers of bone turnover and iliac crest biopsy specimens obtained before and 3 years after E2 replacement. Twenty-one women with Turner's syndrome, aged 20-40 years, were studied. The T scores of bone mineral density at lumbar spine and proximal femur at baseline were -1.4 and -1.1, respectively. Hormone replacement was given as subcutaneous E2 implants (50 mg every 6 months) with oral medroxy progesterone. Serum E2 levels increased incrementally from 87.5 pM at baseline to 323, 506, 647, and 713 pM after 6 months and 1, 2, and 3 years of hormone replacement therapy (HRT), respectively. The bone mineral density at the lumbar spine and proximal femur increased after 3 years to T scores of -0.2 and -0.4, respectively. The cancellous bone volume increased significantly from 13.4% to 18.8%. There was a decrease in activation frequency, but the active formation period was increased by HRT. There was a significant increase in the wall thickness from 33.4 microm at baseline to 40.9 microm after 3 years of HRT, reflecting an increase in bone formed at individual remodeling units. Although there was an early increase in biochemical markers of bone formation, these declined thereafter. Our results show that estrogen is capable of exerting an anabolic effect in the skeleton of young women with Turner's syndrome and low bone mass.

The anxiety regarding no-bleed regimens is that breakthrough bleeding and endometrial hyperplasia may occur. We aimed to demonstrate that 25 mg oestradiol implants can be adequately opposed by a low dose of progestogen protecting against osteoporosis. Twenty-two patients were recruited to the study. The mean age was 62 years and body mass index of 26.5. Median oestradiol rose from 77 pmol/L at baseline to 275 pmol/L at one year. Median endometrial thickness remained unchanged at 4 mm and only two women withdrew with bleeding problems. There was one case of proliferative endometrium at one year--all others samples were either atrophic or secretory. Lumbar bone density (L2-L4) rose significantly from 0.939 to 0.992 g/cm2 (6%, P = 0.005) and the total femoral density rose from 0.872 to 0.890 g/cm2 (+2.1%). Bone formation markers increased significantly (serum type 1 procollagen C terminal peptide, P1CP = 112-114, P = 0.0376) and bone resorption fell (serum type 1 collagen C terminal telopeptide, 1CTP = 3.0-2.9, P = 0.2863). E25 implants and low dose progestogen appear to avoid endometrial hyperplasia and bleeding problems while increasing bone density.

Background: The biologically active component of a hormone is the unbound or free fraction. Changes in cortisol-binding protein could give misleading results if only total cortisol is measured for the interpretation of dynamic function tests., Methods: This study aimed to measure serum free cortisol using a steady-state gel-filtration method and then to evaluate the correlation between the serum free cortisol and the free cortisol index (FCI), defined as serum total cortisol/cortisol-binding globulin (CBG)., Results: Forty-eight serum samples from healthy volunteers undergoing a short Synacthen test were analysed for total cortisol, free cortisol and CBG. The FCI correlated well with a previously established, but more complex, calculation of serum free cortisol (R = 0.98, P <0.001) and with measured serum free cortisol (R = 0.90, P < 0.001)., Conclusion: Free cortisol index is a reliable and user-friendly measure of serum free cortisol.

Objectives: To test the hypothesis that the increased bone turnover observed in established pre-eclampsia is present earlier in pregnancy prior to the diagnosis of pre-eclampsia., Design: A prospective longitudinal study., Setting: Obstetric Unit at Chelsea and Westminster Hospital, London., Population: Nine women who subsequently developed pre-eclampsia and 17 normal pregnant controls., Methods: Maternal plasma levels of the cross-linked carboxyl terminal telopeptide of the type I collagen (ICTP), a marker of bone resorption, and of the carboxy-terminal propeptide of type I collagen (PICP), a marker of bone formation, were measured longitudinally in nine women who developed pre-eclampsia and 17 women with normal pregnancy. Serial blood samples were obtained at 16, 20, 24, 28, 32 and 36 weeks of gestation and the levels of ICTP and PICP were measured by radio-immunoassay., Results: ICTP and PICP increased progressively in the normal pregnant and pre-eclampsia groups, but the rate of increase was significantly greater in the latter (P = 0.00002 and 0.0008, unpaired t test, for ICTP and PICP summary measures, respectively). In the pre-eclampsia group, positive correlation were observed between ICTP levels at 36 weeks of gestation and plasma uric acid (r = 0.9, P = 0.001) and degree of proteinuria (r = 0.78, P = 0.04). No correlation was observed between the two bone markers and other variables during normal pregnant group., Conclusion: These data show that biochemical markers of bone turnover are greater in pregnancies complicated by pre-eclampsia compared with normal pregnancy but only when the disease is clinically evident.

There has been little evidence to indicate that arginine is the natural substrate for generating nitric oxide synthase (NOS) activity. It is now shown that carnosine, which is widely distributed in tissues, is likely to be the true substrate. In tissue sections it gives a stronger NOS reaction than does arginine., (Copyright 2001 John Wiley & Sons, Ltd.)

Objective: To construct gestation-specific reference intervals for fetal concentrations of biochemical markers of bone metabolism and assess the effect of rhesus isoimmunisation on these., Methods: Fetal blood samples were obtained by cordocentesis from 175 pregnancies (43 complicated by rhesus isoimmunisation) and assayed for carboxy terminal pro-peptide of type I pro-collagen (PICP) and cross-linked carboxyterminal telopeptide of type I collagen (ICTP) which directly monitor the rate of bone formation and resorption respectively., Results: Both plasma PICP and ICTP were negatively correlated with gestational age (r = -0.351 and -0.472 for PICP and ICTP, respectively, and P < 0.001 for both). In fetuses affected by rhesus isoimmunisation PICP levels were lower (P=0.030) and more variable (P <0.001) than expected, compared with normal unaffected fetuses. However, no such differences were found in the ICTP levels. In the fetuses affected by rhesus isoimmunisation there was a significant correlation between haemoglobin concentration and both PICP (r = 0.504, P = 0.001) and ICTP (r = 0.343, P = 0.030)., Conclusions: Fetal bone turnover declines from early second trimester to term, and may be deranged in fetuses affected by rhesus isoimmunisation.

Objectives: To investigate the hypothesis that bone turnover is reduced in pre-eclampsia compared with normal pregnancy., Design: A prospective cross-sectional study., Setting: Obstetric unit at the Chelsea and Westminster Hospital, London., Methods: Third trimester maternal plasma levels of the cross-linked carboxyl-terminal telo-peptide of type I collagen (ICTP), (a marker of bone resorption) and the carboxyl terminal pro-peptide of type I pro-collagen (PICP), (a marker of bone formation) were compared in 25 women with pre-eclampsia and in 24 normal pregnant controls. The subjects were matched for maternal age, booking body mass index and gestational age. PICP and ICTP levels were measured by radio-immunoassay., Results: ICTP and PICP levels were significantly increased in women with pre-eclampsia compared with the normal pregnant controls (P = 0.0001 and P = 0.004, for ICTP and PICP respectively, Wilcoxon signed ranked test). There was no significant correlation between either of the markers and booking body mass index, blood pressure, serum uric acid levels or platelet count., Conclusions: These data suggest that bone turnover is increased in established pre-eclampsia compared with normal pregnancy. Further studies are required to investigate whether this precedes the onset of the disease.

It is well recognized that estrogen (E(2)) prevents postmenopausal bone loss by suppressing bone resorption. Despite evidence that E(2) may also stimulate bone formation in animals, an anabolic effect in humans is still controversial. To investigate this, we studied 22 older postmenopausal females, with a mean age of 65.4 yr and mean interval of 16.9 yr since menopause and low bone mineral density. Transcortical iliac bone biopsies were performed before and 6 yr after E(2) replacement therapy (ERT) [75 mg percutaneous E(2) replaced 6-monthly plus oral medroxy progesterone acetate (5 mg daily) for 10 days each calendar month]. The mean serum E(2) level after 6 yr of treatment was 1077 (range, 180-2568) pmol/L. Bone mineral density improved in every patient, with a median increase of 31.4% at the lumbar spine and 15.1% at the proximal femur. Bone histomorphometry showed an increase in cancellous bone volume from 10.75% to 17.31% (P < 0.001). The wall thickness after 6 yr of E(2) treatment was 38.30 micrometer compared with 31.20 micrometer before commencement of ERT (P < 0.0005), indicating net bone gain. This is the first report showing histological evidence for an increase in cancellous bone volume, together with an increase in wall thickness, in a longitudinal follow-up study of ERT in older postmenopausal women. Our results show that E(2) is capable of exerting an anabolic effect in women with osteoporosis, even when started well into the menopause.

Background: Insulin resistance is associated with ischaemic heart disease and has been proposed as a risk factor for subsequent myocardial infarction., Aim: To investigate the potential use of a recently proposed insulin resistance index in identifying insulin resistance in patients admitted with an acute coronary syndrome., Methods: Single centre study of 441 non-diabetic patients admitted with chest pain to a coronary care unit and followed prospectively for a median of three years for outcome. Admission glucose and insulin concentrations were measured and from these values an admission index of insulin resistance (AIRI) calculated. Its association with other known factors in the insulin resistance syndrome, and subsequent outcome, was examined., Results: The AIRI was greater in patients with myocardial infarction than in a control group without myocardial infarction (p < 0.0001). A Cox regression model for subsequent cardiac death identified previous myocardial infarction (p < 0.0001), infarct size (p < 0.0001), and AIRI (p = 0. 0033) as positive risk predictors. Patients of Indian subcontinent ethnic origin had greater AIRI values than white patients: mean (SD) 7.5 (1.3) v 4.6 (0.2), p < 0.001., Conclusions: A simple index of insulin resistance measured on patients admitted with myocardial infarction provides an important predictive measure of poor outcome and is superior to admission glucose measurement. It may be useful in identifying patients admitted with myocardial infarction who could benefit from alternative early management strategies.

The previous quantitative histochemical method for measuring nitric oxide synthase (NOS) activity in tissue sections involved the loss of about 15 per cent of the NOS, presumably from the section into the reaction medium. Two changes are now described. The first is concerned with the preparation in the laboratory of the active reagent, lead ammonium citrate/acetate (LACA). The second change involves an improvement of the procedure for measuring NOS activity. The new method appears to retain all the measurable NOS activity inside the section., (Copyright 1999 John Wiley & Sons, Ltd.)

There is evidence that infants of insulin-dependent diabetics have increased intrauterine bone resorption and reduced bone mineral content at birth. The aim of this study was to determine if type I diabetes is associated with abnormal maternal bone metabolism. We measured the circulating levels of carboxyterminal propeptide of type I procollagen (PICP) and cross-linked carboxyterminal telopeptide of type I collagen (ICTP) in the third trimester of pregnancy in samples obtained from 19 pregnant women with type I diabetes and 19 pregnant controls, to monitor the rate of bone formation and degradation, respectively. Diabetic control was considered to be good as the mean hemoglobin A(1) level was less than 8.5%. The circulating levels of PICP were significantly higher in pregnant women with insulin-dependent diabetes than in controls with uncomplicated pregnancy (median IDDM 147 microgram/liter, control 115 microgram/liter, P = 0.0014), but there was no significant difference in the circulating levels of ICTP between the two groups (median IDDM 4.6 microgram/liter, control 4.6 microgram/liter, P = 0.907). Therefore, our findings suggest that there is an increase in bone formation in pregnant women with type I diabetes which may be related to the increased amount of insulin administered and the improvement in diabetic control associated with pregnancy.

The optimal method for assessing the hypothalamic-pituitary-adrenal axis (HPA) remains controversial. The insulin tolerance test (ITT) is considered the gold standard, but is invasive and potentially dangerous. The short Synacthen test (SST) is the most commonly used alternative, but its concordance with the ITT is poor. Using sleep as a reliable stimulus to ACTH release, we proposed that the increment in urinary cortisol levels between midnight and waking could provide a noninvasive, physiological means for the assessment of the HPA axis. Double voided urine samples were collected at home at midnight and waking in 40 patients with pituitary disease and 40 controls. Cortisol and creatinine levels were measured, and the cortisol/creatinine (Cort/Cr) ratio was calculated. The Cort/Cr increment was defined as the morning Cort/Cr ratio minus the midnight Cort/Cr ratio. The Cort/Cr increment of the patients was compared to the results of their ITT or SST. Using the results from the 40 controls, a normal Cort/Cr increment was defined as greater then 9. The positive predictive value of a Cort/Cr increment for the diagnosis of HPA insufficiency was 95%. These findings suggest that the midnight to morning Cort/Cr increment is a reliable, noninvasive alternative to the ITT/SST for assessment of the HPA.

We re-examined, in the context of modern practice, plasma insulin and stress hormone concentrations in patients admitted to hospital with acute coronary syndromes. Venous blood sampling was carried out prior to anti-thrombotic therapy in 148 patients with myocardial infarction (MI); 76 patients with unstable angina (UA) pectoris were also studied, together with 27 patients with non-cardiac chest pain (NCP). There were significant progressive increases in the concentrations of catecholamines, cortisol, glucose and insulin from NCP to UA to MI patients. Hyperglycaemia (glucose >8 mmol/l) was present in over 50% of MI patients. The plasma cortisol and insulin levels were both significantly positively correlated with the glucose concentration on admission. Only the cortisol concentration was correlated with peak cardiac enzyme levels. The glucose and insulin concentrations on admission in 141 MI and UA patients were related to insulin resistance, as judged from subsequent insulin and glucose concentrations measured while fasting and during a glucose tolerance test. The product of admission insulinxglucose (divided by 25; the admission insulin-resistance index, or AIRI) was significantly correlated with indices of insulin resistance, and was significantly higher (approximately double) in the MI group (7. 81+/-0.76) and the UA group (6.88+/-1.19) than in the control NCP group (3.59+/-0.06; Kuskul-Wallis: P=0.0001), implying that the insulin levels in the first two groups were approximately twice as high as is appropriate for the glucose levels. The ethnic origin of 20% of the patients was the Indian subcontinent; admission insulin and glucose levels in this subgroup were higher than in the non-Asians across all the groups with chest pain. Cortisol was the only stress hormone that was raised in proportion to the size of the infarct, and is a likely partial cause of the elevation in blood glucose. The high insulin levels were related to the prevalence of insulin resistance, and this was particularly important in the Asian subgroup presenting with MI and UA. Thus it appears feasible to identify acute coronary syndrome patients who are insulin-resistant at a time (on admission) when alternative early therapeutic strategies can be instituted.

Objective: Acne vulgaris is androgen related and in some cases is associated with excess androgen production, which in men would be mainly testicular or adrenal in origin. Ordinarily, testosterone synthesis in the testis is controlled by serum LH. In order to ascertain whether acne vulgaris in men might be consequent on abnormalities at the hypothalmic/pituitary level we have compared serum LH levels in men with and without acne., Design and Patients: 111 men with acne vulgaris were compared with 51 acne-free men., Measurements: Serum levels of LH, FSH and oestradiol were measured by automated ELISA. Dehydroepiandrosterone sulphate (DHEA-S), 17 alpha-hydroxyprogesterone, 11-deoxycortisol, androstenedione and testosterone were measured by radioimmunoassay, and SHBG by immunoradiometric assay., Results: The controls showed a fall in serum LH with age: the rate of fall was less in the acne patients (difference between the slopes 0.073 U/year (95% confidence interval (CI), 0.016 to 0.130)). The age distributions in the acne and control groups differed. In order to compare means, standardizations were used to assess the difference in the means in populations of men with age distributions similar to the cases and controls. After standardization to the age distribution of the controls, the acne patients had higher means of serum LH, difference between the means 0.80 U/I (95% CI, 0.31 to 1.30), androstenedione, 1.09 nmol/l (95% CI, 0.15 to 2.03) and testosterone levels, 2.74 nmol/l (95% CI, 0.53 to 4.95) and a lower mean BMI, -1.30 kg/m2 (95% CI, -2.40 to -0.19). After standardization to the age distribution of the acne patients the means of LH, androstenedione and testosterone were still higher in the acne patients but not necessarily significantly so., Conclusion: LH fell more slowly with age in the men with acne as compared to the controls. In our heterogeneous group of patients with acne vulgaris the findings suggest that a sub-group of men with acne have raised serum LH levels.

The aim of this study was to determine whether the current regimen of dexamethasone administration to induce fetal lung maturation affected the circulating concentrations of placental hormone. A standard regimen of dexamethasone that comprised two doses of 12-mg intramuscular injections, 12 h apart was administered to 12 pregnant women to promote fetal lung maturation in anticipation of premature delivery before 34 completed weeks of gestation. Blood samples were collected before starting the dexamethasone therapy, 24 h, and 48 h after completing therapy for the measurement of the plasma concentrations of human chorionic gonadotrophin (HCG), oestradiol and progesterone. There was a progressive fall in the plasma concentrations of HCG following dexamethasone therapy (P = 0.049 and P = 0.034, 24-h and 48-h post therapy respectively). There was an initial fall in the plasma concentrations of oestradiol after dexamethasone therapy (z = 3.059; P = 0.002, 24-h post therapy), which recovered by 48 h (P = 0.239). There was no difference between the plasma concentrations of progesterone at the three time points. The effect of dexamethasone on HCG concentrations suggests that it has a direct inhibitory effect on placental hormone synthesis or secretion. Further studies are needed to define the mechanism of action of dexamethasone on placental HCG production.

Objective: To assess the risk of maternal osteoporosis associated with antenatal corticosteroid administration for neonatal respiratory distress syndrome prophylaxis., Design: Prospective longitudinal study., Setting: Maternity unit of Chelsea and Westminster Hospital, London., Population: Fourteen pregnant women who received dexamethasone therapy for fetal lung maturation in anticipation of delivery before 34 completed weeks of gestation., Methods: Blood samples were collected before dexamethasone administration, 24 hours and 48 hours after the course of dexamethasone, and within 24 hours of delivery. Serum levels of carboxy terminal pro-peptide of type I pro-collagen (PICP) were measured to monitor the rate of bone formation, and serum levels of cross-linked carboxy terminal telopeptide (ICTP) were measured as a marker of bone resorption., Main Outcome Measures: Changes in the markers of bone turnover following dexamethasone administration., Results: Serum PICP levels dropped 24 hours after dexamethasone therapy (P = 0.001), but partially recovered by 48 hours (P = 0.014) to reach higher than pre-therapy levels at delivery (P = 0.044). Although there were no corresponding changes in the serum levels of ICTP after 24 and 48 hours of therapy, levels increased from pretherapy to delivery (P = 0.006)., Conclusion: Antenatal corticosteroid therapy leads to a transient suppression of, followed by an increase in, bone formation without any significant alteration in the pattern of bone resorption expected during pregnancy.

Human and rat plasma and rat hypothalamus contain a cytochemically detectable substance, the concentration of which rises with an increase in salt intake. The plasma concentration of this material is also raised in essential hypertension and in the spontaneously hypertensive rat (SHR), the Milan hypertensive rat, and the reduced renal mass (RRM) hypertensive rat. In the normal rat, the greatest concentration is found in the hypothalamus of the SHR and the RRM hypertensive rat. The physicochemical characteristics of this cytochemically detectable hypothalamic hypertensive factor (HHF), including chromatographic behavior and molecular weight range, suggest that it may share features common to a substituted guanidine that is present in established nitric oxide synthase (NOS) inhibitors. It was therefore decided to determine the effect on NOS activity of the HHF obtained from mature SHR. The ability of HHF to inhibit NOS activity was studied on (1) NOS extracted from bovine aorta, rat brain, and human platelets by measuring the conversion of radiolabeled L-arginine to L-citrulline and (2) rat liver NOS measured indirectly with a cytochemical technique based on the stimulation of soluble guanylate cyclase activity in hepatocytes by NO. HHF showed a biphasic inhibitory action on platelet NOS activity that was greater with HHF obtained from SHR than from Wistar-Kyoto rats. HHF also had a biphasic inhibitory effect on hepatocyte NOS activity that was more potent when obtained from SHR. It is proposed that the increase in HHF, a novel form of NOS inhibitor that is elevated in SHR, may be involved in the rise in arterial pressure.

We have investigated the hormone profiles and the relationship between serum testosterone and luteinizing hormone in men with long-standing acne vulgaris. In the controls, age correlated with the free androgen index and with serum dehydroepiandrosterone-sulphate, so for the purposes of comparison 33 men with acne vulgaris were age-matched against 33 controls. Compared with controls, the acne patients had higher medians of serum androstenedione, testosterone and free androgen index. In both groups there was a significant correlation between testosterone and luteinizing hormone levels. For a given level of luteinizing hormone the patients with acne tended to have higher levels of serum testosterone than normal controls. These results indicate that in this group of men with long-standing acne there was either increased responsiveness of the target organ to luteinizing hormone or there was an increased amount of androgen-secreting tissue.

Hypothalamus and plasma of salt-loaded rats, spontaneously hypertensive rats (SHR), and hypertensive reduced renal mass rats (RRM), and the plasma of patients with essential hypertension and of Milan hypertensive rats contain an increased concentration of a cytochemically detectable glucose-6-phosphate dehydrogenase (G6PD)-stimulating substance that has properties similar to that of a possible choline derivative di-methyl methylene immonium ion. Intracerebroventricular (i.c.v.) administration of hemicholinium-3 (HC-3) selectively blocks high-affinity neuronal choline uptake, inhibits brain acetylcholine (ACh) synthesis, and decreases arterial pressure in SHR through an inhibiting effect on hypothalamic cholinergic function. The experiments were performed to study the effect of centrally administered HC-3 on the content of the cytochemically detectable cholinelike substance in hypothalamus and plasma of SHR. HC-3 or saline was infused into the lateral cerebral ventricle for 6 days with a minipump in 14 SHR. On day 7, the hypothalamic and plasma concentration of the cytochemically detectable substance was significantly reduced in rats that received HC-3. The hypothalamic concentration was 225 +/- 95.6 x 10(8) G6PD U per hypothalamus (range 38.2-775) in SHR that received saline and 1.037 +/- 0.45 x 10(8) G6PD U (range 0.112-3.61) (p < 0.05) in SHR that received HC-3. The respective plasma concentrations were 284.9 +/- 26 U/ml (range 192-374) and 72.7 +/- 14.7 U/ml (range 24-119) (p < 0.05). The findings are consistent with the physicochemical evidence, which suggests that the cytochemically detectable substance is a choline derivative.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma from normal humans and rats on a high sodium intake, and from patients and rats suffering from hereditary hypertension has an increased cytochemically detectable glucose-6-phosphate dehydrogenase (G6PD)-stimulating/Na-K-ATPase inhibiting activity. The hypothalamic content of this activity is also increased by a high sodium intake and in the spontaneously hypertensive rat (SHR). Using cytochemical techniques, the ability of plasma and the hypothalamus of reduced renal mass hypertensive rats to stimulate G6PD activity and to inhibit Na-K-ATPase was measured. The mean G6PD-stimulating capacity of the plasma from the hypertensive and normotensive groups of rats was 351 +/- 67 and 11.42 +/- 1.98 G6PD-stimulating units/mL respectively (P less than .001). The time courses of the ability of plasma from a hypertensive and a normotensive rat to inhibit fresh tissue Na-K-ATPase after 2, 4, 6, and 8 min of exposure demonstrated that the hypertensive rat plasma had a greater capacity to inhibit Na-K-ATPase. The mean G6PD-stimulating capacity of the hypothalamus from the hypertensive and normotensive groups of rats was 252,263 +/- 147,958 X 10(3) and 6.38 +/- 2.35 X 10(3) G6PD-stimulating units per hypothalamus, respectively (P less than .01). It is proposed that the raised concentration of cytochemically detectable G6PD-stimulating/Na-K-ATPase-inhibiting substance in both genetic and nongenetic forms of hypertension may be a manifestation of a communal hypertensinogenic mechanism. Thus, the raised plasma concentration would have a direct peripheral vascular constricting effect and the high hypothalamic concentration would be responsible for a central nervous hypertensinogenic effect.

The oestrogen receptor content of colorectal adenocarcinoma was investigated using an established ligand binding biochemical assay and two more recently introduced techniques using specific monoclonal antibodies (Abbott ER-EIA and ER-ICA assay kits). Twenty nine tumours were investigated by the ligand binding assay. Only one (3.4%) tumour gave a weakly positive result (11 fmol/mg cytosol protein); the rest were all negative. Where sufficient tissue was available, the receptors were also determined by a quantitative immunoassay in 18 patients and an immunohistochemical method in 13 patients. The results were similarly all negative. It is concluded that most colorectal carcinomas, irrespective of sex, are oestrogen receptor negative, and it is thus unlikely that hormonal manipulation would have an influence on the course of the disease.

A highly sensitive cytochemical bioassay has been developed for measuring angiotensin II in human plasma. The assay depends on the ability of angiotensin II to alter the reducing potency of the zona glomerulosa as measured by Prussian blue staining and microdensitometry. An inverse correlation between the intensity of the stain and the logarithm of concentration existed over the range 0.05-5.0 fmol/1 of angiotensin II. The limit of sensitivity of the assay in plasma was 50 fmol/1; the index of precision was 0.07 +/- 0.04 (mean +/- SD; n = 15); and the coefficient of variation of a quality control sample was 34%. The response was specific for angiotensin II; approximately 10(2) times more angiotensin III and approximately 10(6) times more ACTH was required to produce a similar effect. Angiotensin I had no significant activity. A significant inverse relationship existed between sodium intake and bioactive angiotensin II in 5 normal subjects studied on low, normal and high sodium diets. Extremely low levels of angiotensin II were detected in anephric subjects.

Laparoscopy was used to identify the polycystic ovary (PCO) in a group of subfertile women. A third were found to have PCO. These patients had higher levels of luteinizing hormone (LH), testosterone (T) and a higher free androgen index (FAI) than those with normal ovaries. Only 15% of patients with laparoscopic evidence of PCO were obese, hirsute and oligomenorrhoeic. Within the PCO group, hirsutism was strongly associated with obesity and a high FAI. A group of subfertile women with PCO and regular cycles was found who had no other identifiable cause for their infertility. These women had higher follicular phase concentrations of LH and higher FAI than ovulatory women with normal ovaries.

In a 21-year-old woman with McCune-Albright syndrome, acromegaly and hyperprolactinemia with hypopituitarism developed secondary to a large pituitary tumor. Bromocriptine suppressed the secretion of growth hormone and prolactin, with a reduction in tumor size. However, at the age of 8, she already showed evidence of biochemical acromegaly, with a paradoxical rise of growth hormone levels during two glucose tolerance tests, in the presence of a radiologically normal pituitary fossa. These data support the hypothesis that long-standing hypothalamic stimulation may have been responsible for the later development of a pituitary tumor.

Thirty-two ovulatory women had serial ultrasound measurements of uterine volume, endometrial thickness and leading follicular diameter compared with serum oestradiol, testosterone and sex-hormone binding globulin. Follicular diameter, endometrial thickness and uterine volume were significantly correlated with serum oestradiol. The day before ovulation was characterized by maximal values for oestradiol, testosterone, luteinizing hormone, endometrial thickness, uterine volume and leading follicular diameter. Leading follicular diameter and endometrial thickness in particular, appear to be useful parameters to indicate impending ovulation.

Fourteen ovulatory patients undergoing diagnostic laparoscopy had at least 2 samples of clear follicular fluid (FF) collected in the late follicular phase. Dominant follicles contained significantly higher concentrations of insulin-like growth factor-1 (IGF1), oestradiol (E2), progesterone (P) and lower androstenedione (AD) than their matched cohorts. After the luteinizing hormone (LH) surge, a significant increase in dominant FF-IGF1 and FF-P occurred. Log FF-E2 and log FF-P were correlated with both FF-IGF1 and FF volume. Log FF-AD was negatively correlated with FF-volume, FF-E2 and FF-P (but not FF-IGF1). The cohort concentration of FF-IGF1 was correlated with serum IGF1. These results support the hypothesis that IGF1 has a central role in the selection of the dominant follicle.

The concentrations of oestrogen receptors (ER) and progesterone receptors (PgR) were measured in the tumours from 47 patients with advanced primary carcinoma of the breast who were immediately treated by endocrine therapy after confirmatory histology. All patients were followed-up for at least 3 months and 27 patients for 18 months. The ER and PgR content in their primary tumour was correlated with the response to treatment, the duration of remission and the survival rate. The actual concentrations of ER and PgR were found to be better indicators of endocrine responsiveness than the mere presence of these receptors, particularly in the postmenopausal group. The remission rate improved with increasing concentrations of ER but not with increasing concentrations of PgR in the primary tumour. The predictability was enhanced when ER and PgR concentrations were considered together. Patients with ER concentrations above 150 fmol/mg cytosol protein and PgR concentrations above 100 fmol/mg cytosol protein in the same tumour were in remission after 18 months of treatment. At this time, only two of the 14 patients with ER and PgR concentrations below these levels were in remission and six had died of the disease.

Fifty-seven patients who had been receiving maintenance haemodialysis for a mean of 4.6 years were given 0.25-0.5 microgram oral 1,25-dihydroxy (1,25-(OH)2) vitamin D3 or a placebo in a double-blind manner for one to two years. In patients with normal radiographs (mean plasma parathyroid hormone concentration 205 microliterEq/ml) 1,25-(OH)2 vitamin D3 prevented the development of the radiological appearances of hyperparathyroidism. In patients with abnormal radiographs (mean plasma parathyroid concentration 709 microliterEq/ml) 1,25-(OH)2 vitamin D3 arrested or reversed the radiological changes of hyperparathyroidism. Nevertheless, the response was slow and the concentration of the hormone remained considerably raised (mean 445 microliterEq/ml). It is concluded from these results that giving 1,25-(OH)2 vitamin D3 to patients receiving maintenance haemodialysis who have normal hand radiographs or minimal erosions is beneficial. In patients with more advanced hyperparathyroidism parathyroidectomy should be considered unless there is a rapid response.

The effect of epidural blockade on the metabolic and hormonal responses to pelvic surgery was investigated in 14 female patients. Central venous blood samples were collected every 30 minutes and analysed for free fatty acids, glycerol, beta-hydroxybutyrate, acetoacetate, glucose, lactate, pyruvate, cortisol and growth hormone concentrations. There was no change in fat and glucose metabolism except for a transient decrease in lipolysis after 30 minutes of surgery. Cortisol and growth hormone values were significantly increased (p less than 0.01) after 60 minutes. A small but statistically significant increase in blood lactate concentration was observed (p less than 0.01) and the concept of a "metabolic V/Q" abnormality is postulated to explain the lacticacidaemia.

Fifteen ovulating women had serial ultrasound scans to measure follicular, endometrial, and uterine growth, as well as biochemical indices including estradiol (E2) and the free androgen index, throughout a natural and a clomiphene-citrate-induced cycle. Despite higher E2 levels in the 5 days preceding ovulation, the clomiphene cycles were characterized by absence of the normal increase in uterine volume and an inhibition of endometrial thickening. It is proposed that the anti-estrogen effect of clomiphene inhibits the normal cyclical growth of the uterus and endometrium.

Mammary duct ectasia developed in three postmenopausal patients who had had pituitary chromophobe adenomas. The first patient had bilateral duct ectasia that developed 8 and 11 years after hypophysectomy. The second patient, who also had bilateral ectasia, had a prolactin-producing pituitary adenoma for which bromocriptine was prescribed. The ectasia developed in one breast before commencing bromocriptine therapy, and in the other breast 2 years later. The third patient also had a prolactin-producing pituitary adenoma. Unilateral duct ectasia developed while bromocriptine was taken. The ectasia in all patients was very marked and affected all excised ducts. Cholesterol granulomas were sometimes very extensive. These cases suggest a relationship between certain hypothalamic/pituitary disorders, possibly related to prolactin secretion and the development of mammary duct ectasia in postmenopausal patients.

Most assays of thyroid stimulating immunoglobulin (TSI) are unsuitable for the quantitation of TSI during the treatment of Graves' hyperthyroidism because assay insensitivity results in some negative responses. Therefore the sensitive cytochemical bioassay was used to investigate the effect of carbimazole on TSI levels as a possible mechanism for the induction of the increased remission rate which is characteristic of thionamide therapy. Twelve patients were studied before therapy for de-novo Graves' hyperthyroidism; seven patients consented to a detailed prospectively study during block-replace therapy with carbimazole 10mg 6 hourly with a later addition of T3 20 micrograms 6 hourly when biochemically euthyroid. In addition thyroid hormone or T3 suppressed technetium (99m Tc) thyroidal uptake was monitored at between weekly and 3 monthly intervals, as well as the clinical findings, total T4 total T3, TSH, antimicrosomal antibody titers and immunoglobulins IgG, IgM and IgA. TSI was detected in all patients before treatment but there was no correlation with any other pretreatment measurements. During therapy TSI fell (in three different patterns) in 6 out of 7 patients studied for between 14-55 weeks (mean 29 weeks). TSI remained unchanged in one patient. Only the 99m Tc uptake correlated with TSI activity in the treated patients as a group (r = 0.71, p less than 0.001). TSI remained detectable in all patients, even in 4 patients in whom T3 suppression of 99m Tc was demonstrated. There is some evidence for a carbimazole effect lowering TSI activity, however relapse rate did not support this. T3 suppressed 99m Tc uptake may be a sensitive in vivo marker of TSI activity.

During a study of the correlation between the histologic types of breast carcinoma and their hormone receptor contents, eight cases of the alveolar variant of invasive lobular carcinoma were identified, and all had estrogen receptor protein concentrations higher than 400 fmol/mg cytosol protein. Four more cases of the same variant were later prospectively diagnosed and their high estrogen receptor concentrations correctly predicted. All 12 tumors occurred in postmenopausal women. Most (92%) presented in Stage I or II of the disease. None of the patients died of the tumors during the short period of follow-up (median two years). It is concluded that the alveolar variant of lobular carcinoma of the breast is a tumor with consistently high estrogen receptor concentration and probably a low-grade malignancy. It is also suggested that the tumor may be the lobular equivalent of the ductal infiltrating Comedo carcinoma.

Cytosol and nuclear estrogen receptors and cytosol progesterone receptors were measured in 17 primary breast tumors and compared with sex chromatin frequencies. In cases with sex chromatin frequencies of greater than 20% there were 7/7 tumors with cytosol estrogen and progesterone receptors, 6/7 with cytosol and nuclear estrogen receptors, and 6/7 with all 3 receptors. This high proportion of receptor positive cases was not observed at lower sex chromatin frequencies. Sex chromatin frequencies in all the cytosol estrogen and progesterone receptor positive tumors were significantly higher (p less than 0.05) than in the other groups. Our results suggest a possible association between the presence of steroid hormone receptors and sex chromatin frequencies of greater than 20%.

Acute volume expansion endows the plasma with the capacity to cause a natriuresis, to inhibit Na-K-ATPase and to stimulate vascular reactivity. These changes are due to a change in the concentration of two or more substances in the plasma. Atrial natriuretic peptides do not inhibit Na-K-ATPase and they decrease vascular reactivity. The search for the Na-K-ATPase inhibitor has been hampered by the lack of specificity of most assays which demonstrate the presence of many irrelevant Na-K-ATPase inhibitors. Cytochemical bioassays, however, appear to have a certain selectivity. They disclose the presence of a Na-K-ATPase inhibitor in the plasma, the concentration of which is controlled by salt intake but the only known substance so far tested, which these bioassays will detect, is ouabain. The hypothalamus contains the highest concentration of the cytochemically bioassayable inhibitory material and its content is also controlled by salt intake. The substance responsible for the cytochemically bioassayable inhibitory activity in the plasma and the hypothalamus share the same physico-chemical properties and on extraction appear in the same fraction. It is possible therefore, that the Na-K-ATPase inhibitor which is detectable by the cytochemical assays in the plasma and hypothalamus is the same. The concentration of cytochemically bioassayable Na-K-ATPase inhibitory activity is raised in the plasma of patients with essential hypertension, the SHR rat and the Milan hypertensive rat, as is the concentration of atrial natriuretic peptide.(ABSTRACT TRUNCATED AT 250 WORDS)