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Purpose: This cross-sectional study determines the sensitivity of muscle architecture and fat measurements of the rectus femoris (RF) and vastus lateralis (VL) muscles from ultrasound images acquired with varying transducer tilt, using a novel transducer attachment, in healthy adults. Secondary objectives were to estimate intrarater and interrater reliability of image measurement and acquisition, respectively. Methods: Thirty healthy adults participated (15 women and 15 men; 25 [SD 2.5] y). Ultrasound image acquisition was conducted by two raters at different transducer tilts relative to the skin: estimated perpendicular, and five measured angles (80°, 85°, 90°, 95°, 100°) using the transducer attachment. Muscle thickness (MT), subcutaneous fat thickness (FT), pennation angle (PA), and fascicle length (FL) were measured. Sensitivity and reliability were assessed using intra-class correlation coefficients (ICCs) and standard error of measurements (SEMs). Results: MT and FT for RF and VL were not sensitive to transducer tilt. However, PA and FL were sensitive to transducer tilt. MT and FT for both muscles showed high ICCs and low SEMs for intrarater and interrater reliability. For PA of both muscles, standardizing transducer tilt improved interrater ICCs and lowered SEMs. Conclusion: MT and FT measurements of RF and VL acquired at 60° knee flexion are robust to varying transducer tilt angles. PA measurements benefit from standardizing transducer tilt.

As the prevalence of obesity grows worldwide, it becomes an increasing concern in working populations. Ergonomists are faced with the challenge of accommodating workplace layouts to include this worker demographic. This study investigated the relationship between shoulder and low back isometric joint strengths across body mass index (BMI) groups. Additionally, relationships between body fat percentage (BF%), absolute strength, and strength normalized to body mass were examined. Ninety, healthy, working age participants performed 11 functional and isometric joint strength exertions. BMI group influenced normalized strength, as the obese 2+ (BMI >35.0) group had up to 63.1% lower joint strength than all other BMI groups (p < 0.05). Significant strong to moderate negative linear relationships existed between BF% and normalized strength for both males and females, and relationships were stronger for females. These strength deficits highlight the importance of considering body composition during ergonomics analyses and configuration of occupational tasks.

Background Infiltration of muscle with non-lean tissue, such as fat, reduces muscle quality. Ultrasound captures muscle quality through measurement of echogenicity. Given the potential implications of quadriceps muscle quality on physical function, particularly in knee osteoarthritis, the purpose of this study was to investigate the relationship between echogenicity, muscle thickness and subcutaneous fat thickness with the clinical severity of osteoarthritis. Methods Thirty-one women with clinical knee osteoarthritis participated. Rectus femoris and vastus lateralis echogenicity, muscle thickness and subcutaneous fat thickness were measured from ultrasound images of the most symptomatic knee. Clinical severity of osteoarthritis was characterized with pain, self-reported function, six-minute walk test, and knee extensor strength. Correlation coefficients were calculated between muscle and fat architecture outcomes (muscle quality, muscle and fat thicknesses) and osteoarthritis clinical severity outcomes. Findings Data from 25 women were of sufficient quality for analysis. Echogenicity (muscle quality) related to the six-minute walk test for both rectus femoris (r = −0.52, p = 0.02) and vastus lateralis (r = −0.74, p = 0.004), with poorer muscle quality related to lower mobility. Subcutaneous fat thickness was related to the six-minute walk test (rectus femoris, r = −0.61, p = 0.0012; vastus lateralis, r = −0.73, p = 0.003) and strength (rectus femoris, r = −0.46, p = 0.02; vastus lateralis, r = −0.59, p = 0.03). Muscle thickness was not related to any severity outcomes. Interpretation Muscle quality, rather than thickness, is associated with mobility performance in women with knee osteoarthritis. Thus, interventions for osteoarthritis that specifically target muscle quality, rather than size, should be explored.

The zinc-finger protein tristetraprolin (TTP) binds to AU-rich elements present in the 3' untranslated regions of transcripts that mainly encode proteins of the inflammatory response. TTP-bound mRNAs are targeted for destruction via recruitment of the eight-subunit deadenylase complex "carbon catabolite repressor protein 4 (CCR4)-negative on TATA-less (NOT)," which catalyzes the removal of mRNA poly-(A) tails, the first obligatory step in mRNA decay. Here we show that a novel interaction between TTP and the CCR4-NOT subunit, CNOT9, is required for recruitment of the deadenylase complex. In addition to CNOT1, CNOT9 is now included in the identified CCR4-NOT subunits shown to interact with TTP. We find that both the N- and C-terminal domains of TTP are involved in an interaction with CNOT9. Through a combination of SPOT peptide array, site-directed mutagenesis, and bio-layer interferometry, we identified several conserved tryptophan residues in TTP that serve as major sites of interaction with two tryptophan-binding pockets of CNOT9, previously found to interact with another modulator GW182. We further demonstrate that these interactions are also required for recruitment of the CCR4-NOT complex and TTP-directed decay of an mRNA containing an AU-rich element in its 3'-untranslated region. Together the results reveal new molecular details for the TTP-CNOT interaction that shape an emerging mechanism whereby TTP targets inflammatory mRNAs for deadenylation and decay.

OBJECTIVE The aim of this study was to evaluate the effectiveness of a 12-week workplace exercise program on work ability, performance, and patient-reported symptoms in older university employees with knee and/or hip osteoarthritis. METHODS Twenty-four participants with clinical hip and/or knee osteoarthritis were randomized to exercise or no exercise. At baseline and follow-up, several work (work ability, resilience), patient-reported (pain, physical function, depressive symptoms, self-efficacy), and performance outcomes (hip and knee strength, mobility performance) were measured. RESULTS Significant improvements in work ability (P

Background. The Collaborative Group on Hormonal Factors in Breast Cancer has brought together and reanalysed about 90% of the worldwide epidemiological evidence on the relation between risk of breast cancer and use of hormone replacement therapy (HRT). Methods. Individual data on 52,705 women with breast cancer and 108,411 women without breast cancer from 51 studies in 21 countries were collected, checked, and analysed centrally. The main analyses are based on 53,865 postmenopausal women with a known age at menopause, of whom 17,830 (33%) had used HRT at some time. The median age at first use was 48 years, and 34% of ever-users had used HRT for 5 years or longer. Estimates of the relative risk of breast cancer associated with the use of HRT were obtained after stratification of all analyses by study, age at diagnosis, time since menopause, body-mass index, parity, and the age a woman was when her first child was born. Findings. Among current users of HRT or those who ceased use 1-4 years previously, the relative risk of having breast cancer diagnosed increased by a factor of 1.023 (95% CI 1.011-1.036; 2p = 0.0002) for each year of use; the relative risk was 1.35 (1.21-1.49; 2p = 0.00001) for women who had used HRT for 5 years or longer (average duration of use in this group 11 years). This increase is comparable with the effect on breast cancer of delaying menopause, since among never-users of HRT the relative risk of breast cancer increases by a factor of 1.028 (95% CI 1.021-1.034) for each year older at menopause. 5 or more years after cessation of HRT use, there was no significant excess of breast cancer overall or in relation to duration of use. These main findings did not vary between individual studies. Of the many factors examined that might affect the relation between breast cancer risk and use of HRT, only a woman's weight and body-mass index had a material effect: the increase in the relative risk of breast dancer associated with long durations of use in current and recent users was greater for women of lower than of higher weight or body-mass index. There was no marked variation in the results according to hormonal type or dose but little information was available about long durations of use of any specific preparation. Cancers diagnosed in women who had ever used HRT tended to be less advanced clinically than those diagnosed in never-users. In North America and Europe the cumulative incidence of breast cancer between the ages of 50 and 70 in never-users of HRT is about 45 per 1000 women. The cumulative excess numbers of breast cancers diagnosed between these ages per 1000 women who began use of HRT at age 50 and used it for 5, 10, and 15 years, respectively, are estimated to be 2 (95% CI 1-3), 6 (3-9), and 12 (5-20). Whether HRT affects mortality from breast cancer is not known. Interpretation. The risk of having breast cancer diagnosed is increased in women using HRT and increases with increasing duration of use. This effect is reduced after cessation of use of HRT and has largely, if not wholly, disappeared after about 5 years. These findings should be considered in the context of the benefits and other risks associated with the use of HRT.

In a prospective study conducted on the island of Guernsey a cohort of 5162 ostensibly healthy women was enrolled between 1967 and 1976. Blood samples were drawn from each participant, who also completed a questionnaire, which provided information on established risk indicators in human mammary carcinogenesis. Plasma selenium levels were measured in 46 breast cancer cases diagnosed a mean of 11 (S.D. 4) years after entry into the study cohort and in an age-stratified sample of 138 women drawn from the study base. Plasma selenium level in the cases was 109 (28) micrograms/l and in the base sample 103 (22) micrograms/l (95% confidence interval for the overall difference, -2 to 14 micrograms/l). The adjusted relative risk of developing breast cancer in the different quartiles of the selenium distribution was 0.80, 0.79, 0.72 and 1.00, respectively. Thus, in the present study selenium was not a strong indicator of human breast cancer risk.

Normal premenopausal Japanese women have significantly more favourable mammographic parenchymal patterns (Wolfe Grades) than comparable British women. This finding is unaffected when the women are stratified by age, Quetelet's Index, age at menarche, age at first birth, and parity.

The association with breast cancer of menstrual and reproductive events, family history of breast cancer, and body size have been studied on two cohorts of 6,706 volunteers on the island of Guernsey (United Kingdom), 168 of whom had breast cancer detected during follow-up. The median follow-up time of the non-cases was 21 years in the first study and 10 years in the second. A time-dependent Cox regression model was fitted to the data with age as the time-dependent variable in order to represent the effect of changing menopausal status. Other variables examined in the model were age at menarche, parity, age at first birth, family history of breast cancer, height, weight (both directly measured), relative weight (weight [kg]/height[m]), and Quetelet's body mass index (weight[kg]/height[m]2). Interactions between age and all other covariates also were examined. Family history was found to be the most important risk factor for women aged less than 51 years (relative risk [RR] = 3.5, 95 percent confidence interval [CI] = 2.0-6.0), and intervals between menarche and first birth longer than 14 years were found to increase significantly the risk of breast cancer in women older than 61 years (RR = 2.4, CI = 1.3-4.4). Height was the only indicator of body size which was associated significantly with risk of breast cancer, the estimated regression coefficient indicating an increase in risk of about 70 percent for women on the 90th centile of height relative to those on the 10th centile. A survey of the literature showed that the association between risk of breast cancer and height was found in those studies which used direct measurements of height but not in others which used self-reported values.

In 1968-1975, a cohort of 5,100 ostensibly healthy women was established on the island of Guernsey, England, for investigation of the influence of hormonal factors on breast cancer. At the women's entry into the study, blood samples were drawn from each participant, and each woman completed a questionnaire that provided information on established risk indicators in human mammary carcinogenesis. Plasma copper levels were measured in 46 breast cancer cases diagnosed an average of 11 years (standard deviation (SD), 4) after entry into the study cohort and in an age-stratified random sample of 138 women drawn from the total initial cohort at risk. Plasma copper levels were 1.31 mg/liter (SD, 0.37) in the cases and 1.26 mg/liter (SD, 0.36) in the controls; the 95% confidence interval for the overall difference was -0.07 to 0.17. A U-shaped relation between premorbid plasma copper levels and the risk of developing breast cancer was seen. Adjusted odds ratios for breast cancer were 1.8, 1.0, 1.6, and 3.2, respectively, in the four quartiles of the copper distribution. No major changes in the risk estimates were observed when statistical evaluation was restricted to cases diagnosed more than 10 years after collection of blood samples.

Between 1968 and 1976 a total of 5162 women volunteers were enrolled into a prospective study conducted on the Island of Guernsey. Up to February 1990 145 women subsequently developed breast cancer. Blood samples were taken at the time of enrollment and prolactin levels were known for 85% of the volunteers. In calculating the relationship between blood prolactin levels and subsequent breast cancer risk, women were excluded if they had a hysterectomy or an oophorectomy or had cancer at any site before enrollment. The final analysis was based on 2596 premenopausal and 1180 naturally postmenopausal women and, of these respectively, there were 71 and 40 volunteers who subsequently developed breast cancer. The total follow-up for these two groups was 49,941 and 22,360 woman-years, respectively. In assessing the relationship between blood prolactin levels and risk of subsequent breast cancer the cohort was divided into quintiles according to prolactin concentration and relative risks (RR) were estimated. In calculating these values possible confounding by age at entry, age at menarche, parity, age at first birth, years since menopause, body build, history of benign breast disease and family history of breast cancer were taken into consideration. There was no significant relation between risk of breast cancer and prolactin in either pre- or postmenopausal women. Hence prolactin appears not to be an important determinant of breast cancer risk.

The search for an hormonal abnormality as a key determinant of risk of benign breast disease has proved to be as fruitless as that for breast cancer. In both conditions, the initial lesion is likely not to be mediated by the endocrine system. Once normal epithelial cells have been diverted to either a benign or malignant pathway, variations within the normal hormonal range may be sufficient to account for the clinical and biological manifestations of both conditions.

Epidemiological evidence has suggested that cigarette smoking has an anti-oestrogenic effect in women, but the effects of smoking on steroid hormone metabolism are not fully understood. We compared serum concentrations of oestradiol, progesterone (luteal phase) and dehydroepiandrosterone sulphate (DHEA-S), and urinary excretion rates of six steroids of predominantly adrenal origin, in healthy premenopausal and postmenopausal female smokers and non-smokers. Serum concentrations of oestradiol, progesterone and DHEA-S did not differ between smokers and non-smokers by greater than 5%, and none of these differences was statistically significant. Mean urinary excretion rates of androsterone, aetiocholanolone, DHEA, 11-keto-aetiocholanolone, 11-hydroxyandrosterone and 11-hydroxyaetiocholanolone were very similar in smokers and non-smokers in premenopausal women, but were from 2-44% higher in smokers than non-smokers in postmenopausal women. The difference was statistically significant only for 11-hydroxyandrosterone. These results confirm previous reports that cigarette smoking does not affect serum oestradiol in premenopausal or postmenopausal women, but provide only weak evidence to support previous findings of increased levels of some adrenal steroids in postmenopausal women smokers. The mechanism for the apparent anti-oestrogenic effect of cigarette smoking remains unclear.

Abnormalities in endocrine function are not a determinant of risk of breast cancer within countries, and racial differences in this function do not explain geographical variation in risk. It is suggested that hormonal status is related to tumor growth rates and hence to age at diagnosis, recurrence rates after primary treatment, and survival. Such evidence as there is points in this direction, but it still remains to be finally established whether the disease runs a similar course in all countries when patients are standardised for factors known to affect prognosis.

More than five years of tamoxifen is no longer justified A major clinical trial of long term adjuvant treatment with tamoxifen in women with primary breast cancer has been stopped by the National Cancer Institute of America on the grounds that treatment for more than five years is unlikely to be beneficial.1 The institute's report relates to trials carried out by the National Surgical Adjuvant Breast and Bowel Project in Pittsburgh. Between 1981 and 1993 over 4000 women who had undergone surgery with or without radiotherapy for oestrogen receptor positive breast cancer but who had no lymph node involvement were recruited into two randomised clinical trials. The first of these examined the effect on survival of adjuvant therapy with tamoxifen. Ten years after primary treatment, patients receiving the drug had an overall survival of 78% compared with 75% in the placebo group, results which are in line with those in an overview of 133 randomised controlled trials published in 1992.2 The difference, while small, is significant. Whether …

The amounts of urinary androsterone and etiocholanolone are highly correlated with recurrence rates in patients with early breast cancer after treatment by mastectomy. A more efficient means of predicting the clinical course of the disease is obtained by using a ratio of these compounds to the amounts of individual 17-hydroxycorticosteroids in the urine. For instance, the ratio of androsterone to alpha-cortolone is particularly effective in identifying women with a high rate of recurrence, and this is largely independent of pathological stage and tumor grade.

SynopsisA wide variety of methods has been used to investigate the role of the oestrogens in the aetiology and clinical course of breast cancer. They include measurements of urinary metabolites and the concentrations of oestrogens in blood, saliva, nipple aspirates, cyst fluids, lymph and breast tissues. The function of the oestrogen-binding proteins has also been examined. There is no clear evidence that an excessive oestrogenic stimulus is a determinant of risk of breast cancer and it may be sensible to question this widely-held belief. Variation in the oestrogenic stimulus within the normal range might be responsible for the observed differences in tumour doubling times and for clonal selection. Case/control studies which do not include some measure of tumour growth rates are not an efficient way of investigating these possibilities. Endogenous androgen concentrations show such a strong correlation with the natural history of the disease that it would seem unwise to investigate the role of the oestrogens without taking the androgens into account. Geographical variation in the incidence of breast cancer is probably not due to racial differences in endocrine function.

The concentration of circulating ferritin was measured in 250 normal adult women and 229 women presenting with early breast cancer. Ferritin concentrations are higher in cancer patients than in normal women. Patients with an intial circulating ferritin concentration above 200 mug/1 have a higher tumour recurrence rate during the subsequent 4 years.

Mammograms were obtained from 942 normal women aged over 30 years, and were classified by Wolfe's criteria. In women with an enhanced risk of breast cancer associated with a late age at first child or nulliparity, there was a significant increase in the proportion of P2 and DY mammographic patterns which are thought to be a radiological index of risk. There was a decrease in the proportion of P2 and DY grades in women using steroidal contraceptives. However, the association between radiological and epidemiological determinants of risk did not hold for age at menarche.

Following mastectomy, patients aged 35 to 76 years with operable breast cancer underwent postoperative irradiation of the chest wall and regional lymph nodes. They were then assigned at random to receive no further therapy (NT), ovarian irradiation (R) 2000 rads in 5 days, or ovarian irradiation in the same dosage plus prednisone (R + P) 7.5 mg daily for up to five years. A total of 703 eligible patients received the randomly assigned treatment. The median follow up was 21 years with a range of 14 to 25 years. Overall, there was a delay in recurrence (p = 0.03) and survival was prolonged (p = 0.19) for patients who received R, but in neither case was the difference significant after adjusting for the multiplicity in our data. Overall, patients who received R + P experienced a significant delay in recurrence (p = 0.0003) and a significantly prolonged survival (p = 0.005), even after adjusting for multiple comparisons. In premenopausal patients who received R, the recurrence of breast cancer was delayed and survival prolonged, but not significantly. In premenopausal women aged 45 years or more, R + P therapy significantly prolonged survival (p = 0.0004), while the delay in recurrence although significant (p = 0.02) was only marginally so after allowance for multiple comparisons. No value was demonstrated for ovarian irradiation with or without prednisone therapy in postmenopausal patients. A new finding in this review was that contralateral breast cancer as the first failure was reduced by R + P compared to NT in the overall group.

In order to examine the newly-discovered sex-steroid binding protein, foetal steroid binding protein (FSBP) in different populations, its binding characteristics and its level were studied by two-tier column ligand binding assay and enzyme-linked immunosorbent assay (ELISA) respectively. In 10 Japanese premenopausal women, analysis of 5α-dihydrotestosterone (DHT) binding in the Cibacron Blue 3GA-Sepharose 6B portion of the column showed a rising plateau pattern with a mean maximum binding of 31.1 ± 7.41%, whereas of 9 similar British women, 8 displayed unsaturable, non-cooperative binding of 11.6 ± 8.22% (P < 0.01). After partial purification of FSBP in these samples, the protein exhibited saturable binding kinetics, median binding 25 (interquartiles 23–34) and 19 (13–25) nmol DHT/l in Japanese and British women, respectively (P < 0.05). By analyzing FSBP by ELISA in 56 Japanese (45 premenopausal) and 59 British (25 premenopausal) women, higher levels were obtained in the whole Japanese group (P = 0.0016) and in the premenopausal Japanese women (P = 0.018) than in their British counterparts. In both nationalities, FSBP levels were higher in premenopausal women, and there was a significant negative correlation of FSBP with age in both populations, particularly in postmenopausal women. FSBP levels did not correlate with weight, parity, sex hormone binding globulin or albumin levels. The influence of FSBP on free steroid levels remains unclear, but some relationship with ovarian function seems a possibility.

Plasma androgen sulfates were measured in 92 patients with myasthenia gravis. Plasma androgen sulfates were strongly associated with thymic pathology. The presence of germinal centers was associated with decreased androgen levels. A weak but significant positive correlation existed between androgen sulfates and lymphocyte counts. Low lymphocyte counts in patients with germinal centers were associated with subnormal androgen concentrations. Plasma androgen sulfate levels decreased immediately after thymectomy, but overall no significant differences were found between prethymectomy and post thymectomy levels. A trend toward higher concentrations of plasma androgens was noted 5 or more years post thymectomy. Plasma androgen sulfate levels in myasthenia gravis patients with breast cancer were markedly depressed. The lowest androgen sulfate levels were observed in patients who had previous bilateral breast cancer and those who, subsequent to the determination of the steroid sulfates, developed a second primary lesion of the breast.

Women with breast cancer whose blood and urinary androgens are at the lower end of the normal range have an early age at diagnosis, a rapid recurrence rate after mastectomy and tumours that are unresponsive to endocrine therapy. The most plausible explanation for these results is that the androgens are not involved in tumour initiation but control tumour growth rates after the malignant transformation has occurred. If this is so, endocrine case/control studies in which growth rates are not measured are an inefficient way of studying the endocrinology of breast cancer. It is suggested that the oestrogens and androgens should be considered as a single functional unit in future research.

Summary.-Serumsialyl transferase (SST) wasmeasuredin49female patients withadvancedbreastcancerand60femalecontrols. Themean SSTlevel was significantly raised in patients with advanced breast cancer. There wasno correlation between specific sites, ornumbersof sites of metastatic disease and SSTlevels. The patients withadvanced breast cancerwere all treatedwithchemotherapy;in 13/21 respondersthere was a significant fall in SSTand in 2 responders a significant rise in SST.The6 patients whodied after onecourseof chemotherapyhada significantly higher meanSSTthan those surviving longer. SST appearsto lack sufficient specificity tobeof practical value as a markerof response in patients with breast cancer treated bychemotherapy, though constant measurement of changes in SST maybe of usein monitoring drug response. Raised SSTat the commencement of chemotherapymay signify poor prognosis.THE GLYCOSYL TRANSFERASES are a groupofenzymesinvolvedin glycoprotein synthesis; they catalyseadditionof specific

Breast parenchymal patterns have been assessed by the method of Wolfe in a prospective study in Guernsey. Women with P2 or DY grades had approximately four times the risk of developing breast cancer compared with those with N1 or P1 grades. Age, weight, parity and age at birth of first child are all related to the distribution of mammographic patterns. The combination of these variables with Wolfe grades may identify subsets of the population at very high risk.

SUMMARY A gas—liquid chromatographic method is described for the routine determination as the chloromethyldimethylsilyl ethers of plasma dehydroepiandrosterone and androsterone obtained after solvolysis of a steroid sulphate fraction. 5α-Dihydrotestosterone sulphate is used as an internal standard. The levels of dehydroepiandrosterone sulphate and androsterone sulphate have been measured in 61 males and 66 females aged 20 days to 91 yr. The steroid levels show an abrupt rise at the age of about 7 yr. and reach a peak between the ages of 20 and 30 yr. Thereafter they fall with advancing age. The mean level of dehydroepiandrosterone sulphate is significantly higher in adult men than in women but the mean level of androsterone sulphate is similar.

SUMMARY The distribution of cortisol in patients with early or advanced breast cancer and in controls was studied, using a two-compartment model for analysis. The patients with advanced breast cancer had significantly raised pool sizes. There were no significant differences in the ratio of two pools found for patients and controls. This suggests that there are no abnormalities in the transfer processes. There was a significant correlation between the exit rate from the intravascular pool and the production rate of cortisol, showing that there is no major extrahepatic metabolism of this hormone in both controls and in breast-cancer patients.

The uptake of oestradiol-17s by normal and neoplastic human breast tissue has been measured following administration of tritiated oestradiol-17s. Both tissues accumulate and retain oestradiol for up to 5 hours. Tumour tissue accumulates higher concentrations of oestradiol-17s than normal tissue. Dromostanolone propionate inhibits the uptake of oestradiol-17s by the tumour but has no apparent effect on the uptake by normal breast tissue.

SUMMARY The method described by Brown [1955] for the estimation of oestrone, oestradiol-17β and oestriol in urine has been critically investigated. 1. All checks on specificity so far carried out have confirmed that the method is specific for these oestrogens. 2. The method gives recoveries of 70–95%. 3. The precision of the method has been calculated for oestrogen levels between 0·0 and 40·0 μg/24 hr. From the figures obtained the fiducial ranges and percentage errors of determinations and the limits of sensitivity of the method have been calculated. 4. A number of substances which may occur in urine and which interfere in the method are listed.

SUMMARY A variety of 14C and 3H-labelled steroids have been perfused through the human adrenal gland in situ and their metabolic products isolated from adrenal venous blood. Progesterone, dehydroepiandrosterone and cortisol were isolated after infusion of [3H]pregnenolone; 17α-hydroxyprogesterone, dehydroepiandrosterone and cortisol after infusion of [3H]17α-hydroxypregnenolone and [14C]progesterone; androstenedione and cortisol after infusion of [3H]17α-hydroxyprogesterone and [14C]dehydroepiandrosterone; and 11β-hydroxyandrostenedione after infusion of [3H]androstenedione and [14C]cortisol. From a consideration of the incorporation of radioactivity into the metabolic products, the3H: 14C ratios and the tissue pool sizes it was concluded that the major biosynthetic pathway to cortisol in the human adrenal glands was: pregnenolone→ 17α-hydroxypregnenolone → cortisol. Progesterone was not an important intermediary. Androstenedione was mainly formed by way of 17α-hydroxypregnenolone → 17α-hydroxyprogesterone → androstenedione. 11β-Hydroxyandrostenedione was formed mainly from cortisol and only a minor amount came from the hydroxylation of androstenedione.

SUMMARY The production rate of cortisol in patients with early or advanced breast cancer was compared with that of controls of comparable age. The miscible pool of this hormone was raised in advanced breast-cancer patients due to a higher production rate. The plasma clearance of cortisol remained unaffected, resulting in a higher titre of cortisol (both total and unbound) in advanced breast-cancer patients. There was no significant difference in the production rate between the early breast-cancer cases and controls. The binding of cortisol to transcortin was studied in all cases. The amount of unbound cortisol was raised in advanced breast-cancer cases. There was a significant correlation between both total and unbound cortisol and the production rate of this hormone. The latter correlation suggests that there is no abnormality in the hepatic extraction of cortisol in these patients. The metabolic clearance rate was found to be of the order of the blood flow through the liver when unbound cortisol was used for its estimation, showing that it is the unbound cortisol which is removed by the liver.

Secretion rates of dehydroepiandrosterone and its sulphate were measured in three cases of ‘testicular feminization”. The pattern of secretion rates was found to be male, rather than female. Plasma levels of 17-hydroxycorticoids (17-OHCS) and 17-oxosteroids (17-KS) were determined in five patients. The 17-KS were found to be at the upper limit of the normal female range and overlapping the male range. 17-OHCS were found to be at the lower end of the female range. Plasma testosterone levels were definitely in the male range. Total urinary oestrogens were at the upper limit of the male range and lower than the normal female range. However, they were higher than those found in women with primary amenorrhoea. The administration of both ACTH and HCG resulted in a rise in the titre of total urinary oestrogens; however, the rise after HCG administration was greater than that after ACTH treatment. The failure to explain the female phenotype in terms of plasma and urinary hormone studies is discussed.

The widespread occurrence of sulphatases in the Mollusca was first demonstrated by Soda & Hattori (1933 a, b) who showed that these enzymes are mainly concentrated in the digestive glands. That extracts from marine molluscs also possess β-glucuronidase activity was first noted by Dodgson, Lewis & Spencer (1952) who studied the optimum conditions for the activity of this enzyme and arylsulphatase in Patella vulgata (L.) and Littorina littorea (L.) and applied their findings in an investigation of the distribution of both enzymes among various other marine molluscs (Dodgson, Lewis & Spencer, 1953).

SUMMARY 1. The purification step described by Ittrich (1958) has been incorporated in the method of Brown, Bulbrook & Greenwood (1957b) for estimating urinary oestrogens. 2. When the Kober colours given by urinary oestrone, oestradiol-17β and oestriol are extracted with tetrachloroethane containing p-nitrophenol, the decrease in the absorption due to impurities is such that the Kober reaction can be scaled down and micro-cells used in the measurement of the final colours. 3. Amounts of urinary oestrogens as low as 0·5 μg./24 hr. specimen can be measured with a reasonable degree of accuracy and precision. 4. The results with the new method show that the method of Brown et al. (1957b) gives over-estimates of approx. 1 μg. oestrone and 1 μg. oestriol/24 hr. urine specimen when used for the estimation of urinary oestrogens of low titre.

SUMMARY The binding by plasma from man, rabbit and rat of the sulphate esters of dehydroepiandrosterone, testosterone, 17-acetoxypregnenolone and pregnenolone has been studied using equilibrium dialysis. The plasma of these species had a large capacity for binding dehydroepiandrosterone sulphate and testosterone sulphate. A large capacity for binding pregnenolone sulphate and 17-acetoxypregnenolone sulphate was observed with plasma from man and rabbit. The percentage binding of the steroid sulphates studied was higher for human plasma than for rabbit plasma and, in the case of the sulphates of dehydroepiandrosterone and testosterone, for rat plasma. The higher percentage binding by human plasma was confirmed using multiple equilibrium dialysis. Evidence is presented that suggests that the sulphate esters of dehydroepiandrosterone, testosterone and pregnenolone are bound to the same sites. Dehydroepiandrosterone sulphate was displaced by non-steroidal organic sulphates, suggesting that the binding sites involved are not specific for steroid sulphates.

SUMMARY The production rate of cortisol based on both the plasma clearance of the hormone (plasma production rate) and the urinary metabolite method (urinary production rate) was simultaneously measured in early or advanced breast cancer patients and in controls. Higher production of the hormone was observed by both these methods in patients with advanced breast cancer. There was a significant correlation between the plasma production rate of cortisol and its urinary production based on the specific activities of three urinary metabolites, namely, cortisol, tetrahydrocortisol (THF) and tetrahydrocortisone (THE). However, the values obtained for the urinary production rate differed considerably in about one-third of the patients due to differences in the specific activities of THE and THF. It is postulated that, in some cases, there may be a second precursor of urinary THE and THF which contributes significant amounts to the excretion of these metabolites. No correlation was found between the cortisol production rate and urinary total 17-hydroxycorticosteroids (17-OHCS).

SUMMARY Brown's original method [1955] for the chemical determination of oestrone, oestradiol-17β and oestriol in human urine gives inaccurate results when applied to the urine from patients with breast cancer being treated with cortisone after oophorectomy-adrenalectomy or hypophysectomy. This is demonstrated by comparing chemical results with biological assays of the activity in the phenolic fraction of the urine. There is no evidence of any material in the phenolic fraction interfering with the biological assay. Results with the modified chemical method [Brown, Bulbrook & Greenwood, 1957a], which obviates the chemical interference caused by cortisone metabolites in the urine, may still disagree with the biological results. There are two main reasons for this. The modified chemical method is still subject to error if the patients are taking laxatives, though the biological assay is unaffected. Furthermore, most of the patients are excreting amounts of oestrogen at or below the limits of accuracy of the chemical method. In the absence of interference by laxatives, biological and chemical results usually agree when the calculated errors of the chemical method at these low levels of oestrogen excretion are taken into account. Biologically detectable oestrogen was present in the phenolic fraction of the urine from eleven out of fifteen oophorectomized-adrenalectomized or hypophysectomized women.

SUMMARY The excretion of urinary 17-hydroxycorticosteroids and 11-deoxy-17-oxosteroids by normal British and Japanese women has been compared. British women excreted more 17-hydroxycorticosteroids than Japanese women but the difference disappears if corrections are made for body weight. Young British women excreted more 11-deoxy-17-oxosteroids than Japanese women of comparable age. This difference remains after correction for differences in body weight. Japanese women aged 40–59 yr. had a significantly higher ratio of androsterone to aetiocholanolone than British women of the same age.

Mammograms were obtained from 942 normal volunteer women aged over 35 years, and were classified by Wolfe's criteria. There was no relationship between height and mammographic pattern. An increase in weight, whether corrected for height or not, was associated with an increase in the proportion of N grades and a concomitant decrease in DY grade mammograms. This effect reached formal significance in premenopausal women but was highly significant in postmenopausal women. For women who were either above or below their ideal weight there was a significant positive correlation between parity and the proportion of N and P1 mammograms. The slopes of the linear regression for these two groups were the same, although the elevation of the above-ideal weight group was significantly greater. This implies that for any given parity, there are about 16% more N or P1 grades in the above-ideal compared with the below-ideal weight group.