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Biomedical subjects

M J Reed

Publications and source records attributed to M J Reed.

At least 163 records · Page 9Linked to original sources
PubMed1990

Effect of treatment with 4-hydroxyandrostenedione on the peripheral conversion of androstenedione to estrone and in vitro tumor aromatase activity in postmenopausal women with breast cancer.

The effect of treatment with the aromatase inhibitor, 4-hydroxyandrostenedione (4-OHA) on the peripheral conversion of androstenedione to estrone has been examined in eight postmenopausal women with advanced breast cancer. Before treatment conversion of androstenedione to estrone ([p]AEIBB) ranged from 0.81 to 3.7% and was almost completely inhibited after treatment with 4-OHA (two doses of 500 mg i.m. with an interval of 12 days between doses). Transfer constants were also measured by the urinary method ([p]AEIBU) for some subjects and decreased from 2.3 +/- 0.52% to 0.24 +/- 0.11% after treatment, a mean reduction of 90%. Mean plasma concentration of estradiol (37.4 +/- 16.6 pmol/liter) and estrone (99.0 +/- 32.2 pmol/liter) decreased significantly (P less than 0.01) to 15.7 +/- 4.6 pmol/liter and 52.4 +/- 8.9 pmol/liter, respectively, after treatment. Aromatase and DNA polymerase alpha (a marker of cell proliferation) activities were measured in seven samples of breast tumor tissue obtained before and after treatment. For three samples there was a marked (67 +/- 17%) decrease in tumor aromatase activity after treatment, for two, little change occurred, while tumor aromatase activity in the other two samples appeared to be resistant to the effect of 4-OHA. The correlation between tumor aromatase and DNA polymerase alpha activities (r = 0.45) failed to reach a significant level.

Aged↗
PubMed1990

Epidermal growth factor and oestradiol in human breast cyst fluid.

Gross cystic breast disease is a common condition in women. Women with apocrine breast cysts (breast cyst fluid Na+/K+ less than 3) may be at higher risk of breast cancer than women who have cysts lined by flattened epithelium (Na+/K+ greater than or equal to 3). Breast cyst fluid concentrations of epidermal growth factor were significantly higher in the low electrolyte ratio group than in the high electrolyte ratio group (356.2 ng/ml vs 104.1 ng/ml, P less than 0.0003). A negative correlation was obtained between intracystic epidermal growth factor concentrations and Na+/K+ (rs = -0.666, P less than 0.001). No significant difference was found between the total oestradiol concentrations in the two cyst groups. However, the unbound oestradiol concentrations on a limited number of samples were significantly higher in the low electrolyte ratio group than in the high electrolyte ratio group (P less than 0.05). The higher concentrations of EGF in cyst fluid with Na+K+ less than 3 may explain why women with apocrine breast cysts may be at increased risk of developing breast cancer.

Apocrine Glands↗
PubMed1990

In vivo conversion of norethisterone to ethynyloestradiol in perimenopausal women.

The extent to which norethisterone is converted to ethynyloestradiol is controversial. To investigate the conversion of norethisterone to ethynyloestradiol we have used a double isotope infusion technique to measure the conversion in vivo. The use of acids or bases was precluded to prevent possible artefactual formation of phenolic metabolites of norethisterone. Transfer constants for the conversion of norethisterone to ethynyloestradiol in two perimenopausal women were 2.26 and 2.34% as measured in blood and 2.27 and 0.38% in urine. Results from this study show that a small but significant proportion of norethisterone is converted to ethynyloestradiol in vivo.

Biotransformation↗
PubMed1990

Analysis by DNA polymerase alpha activity of human breast tumour proliferation and the effect of endocrine therapy.

Cytosols of human breast tumours have been assayed for DNA dependent DNA polymerase alpha activity. DNA polymerase alpha activity in benign tumours was found to be significantly lower than in untreated malignant tumours. Biopsy samples removed surgically before and after endocrine therapy showed reduced DNA polymerase alpha activity in 6 out of 9 patients treated with 4-hydroxyandrostenedione, and in 6 out of 7 patients treated with MPA. DNA polymerase alpha activity in malignant breast tumours was higher in oestrogen receptor negative than oestrogen receptor positive tumours.

Androstenedione↗
PubMed1990

Differences in clinical and endocrine features between obese and non-obese subjects with polycystic ovary syndrome: an analysis of 263 consecutive cases.

Two hundred and sixty-three women with ultrasound-diagnosed polycystic ovary syndrome were studied of whom 91 (35%) were obese (BMI greater than 25 kg/m2). Obese women with PCOS had a greater prevalence of hirsutism (73% compared with 56%) and menstrual disorders than non-obese subjects. Total testosterone and androstenedione concentrations in serum were similar in the two subgroups but SHBG concentrations were significantly lower, and free testosterone levels higher, in obese compared with lean subjects. In addition, concentrations of androsterone glucuronide, a marker of peripheral 5 alpha-reductase activity, were higher in obese than in non-obese women with PCOS. There were no significant correlations of either SHBG or free testosterone with androsterone glucuronide suggesting that obesity has independent effects on transport and on metabolism of androgen. There were no significant differences between the subgroups in either baseline gonadotrophin concentrations or the pulsatile pattern of LH and FSH secretion studied over an 8-h period. There was, however, an inverse correlation of FSH with BMI, but only in the obese subgroup. In conclusion, the increased frequency of hirsutism in obese compared with lean women with PCOS is associated with increased bio-availability of androgens to peripheral tissues and enhanced activity of 5 alpha-reductase in obese subjects. The mechanism underlying the higher prevalence of anovulation in obese women remains unexplained.

Androgens↗
PubMed1990

Inhibition of oestradiol production by epidermal growth factor in human granulosa cells of normal and polycystic ovaries.

Anovulation in women with polycystic ovary syndrome results from a disorder of FSH-mediated follicular maturation which may involve paracrine modulation of FSH action by intra-ovarian factors. Epidermal growth factor (EGF) is a potent inhibitor of FSH-stimulated oestradiol production in the rat and has also been shown to inhibit aromatase activity in human granulosa cells obtained after superovulation. The purpose of this study was to investigate the action of EGF on granulosa cell function in human ovaries which had not been previously exposed to treatment with exogenous gonadotrophins and to compare the responses in tissue obtained from normal and from polycystic ovaries. Granulosa cells were obtained from antral follicles less than 10 mm in diameter after dissection of unstimulated normal or polycystic ovaries (PCO). Cells were pooled, washed, plated and incubated for 48h in the presence of 10(-7) M testosterone and various doses of human FSH. FSH dose responses were obtained with or without the addition of purified EGF (50 pg/ml). Testosterone in the absence of FSH resulted in a fourfold (range 2-7.5) increase in oestradiol accumulation in the medium after incubation of granulosa cells from both normal and polycystic ovaries. This increase was reversed by addition of EGF. FSH treatment stimulated a dose-related increase in oestradiol regardless of the origin of the granulosa cells. The peak E2 response to FSH, obtained at a dose of 1-2.5 ng/ml was a 20-fold increase above testosterone alone (range 4-55) in cells from PCO compared to sixfold (2.5-13) in cells from normal ovaries.(ABSTRACT TRUNCATED AT 250 WORDS)

Cells, Cultured↗
PubMed1990

Effect of insulin-like growth factor-type I (IGF-I) and insulin on the secretion of sex hormone binding globulin and IGF-I binding protein (IBP-I) by human hepatoma cells.

Dietary factors are known to modulate concentrations of sex hormone-binding globulin (SHBG). In the present study we have investigated the possibility that insulin like growth factor-type I (IGF-I) may be an additional regulator of SHBG using cultured human hepatoma cells which secrete SHBG. The inhibitory effect of insulin on SHBG secretion by these cells was confirmed but, in addition, IGF-I was shown to inhibit SHBG secretion by about 40% at a concentration of 100 nmol/l. A similar degree of inhibition was achieved using insulin at a concentration of 10 mumol/l. Insulin, but not IGF-I, was also found to inhibit the secretion of a low molecular weight IGF-binding protein (IBP-I), which is also secreted by hepatoma cells. It is concluded that IGF-I is an additional regulator of SHBG secretion by these cells and that it may be involved in regulating SHBG secretion in vivo in response to dietary factors.

Carcinoma, Hepatocellular↗
PubMed1989

In situ oestrone synthesis in normal breast and breast tumour tissues: effect of treatment with 4-hydroxyandrostenedione.

An isotopic infusion technique has been used in an attempt to determine the contribution that local, in situ, oestrone synthesis makes to the oestrogen content of breast tumours. 3H-Androstenedione and 14C-oestrone were infused into women with advanced breast cancer for 12 hr before operation. At surgery, normal breast and breast tumour biopsy samples were obtained and 3H-androstenedione, 3H-oestrone derived from 3H-androstenedione and 14C-oestrone were isolated and measured. DNA polymerase alpha activity, a marker of cellular proliferation, was also measured to examine whether local synthesis of oestrone exerted a biological effect. The study was repeated after patients had been treated with the aromatase inhibitor, 4-hydroxyandrostenedione, before undergoing further surgery for removal of their tumours. In 4/6 tumours examined, in situ synthesis of 3H-oestrone from 3H-androstenedione accounted for the major part (84.3 +/- 9.0%) of the 3H-oestrone detected, while no significant in situ synthesis occurred in 2 other tumours. Although treatment with 4-hydroxyandrostenedione did not significantly alter the uptake of 3H-androstenedione or 14C-oestrone into breast tissues, in situ formation of 3H-oestrone was only detected in one tumour sample after treatment. DNA polymerase alpha activity decreased in 4/6 tumours after treatment with 4-hydroxyandrostenedione. Overall, however, there was no significant correlation between the level of 3H-oestrone formed in situ and DNA polymerase alpha activity (r = 0.38, NS). It is concluded that in some, but not all, breast tumours in situ formation of oestrone can make an important contribution to the oestrogen content of breast tumours.

Aged↗
PubMed1989

The effects of sequential treatment with ethynyloestradiol and medroxyprogesterone acetate on oestrogen and progestogen receptors in breast cancer.

As part of a clinical study designed to modulate oestrogen and progestogen receptor (ER and PR) binding site concentrations prior to chemotherapy ER and PR levels have been estimated immediately before treatment, after ethynyloestradiol (EE, 10 micrograms/day, 1 week) and after medroxyprogesterone acetate (MPA, 500 mg/day i.m., 2 weeks) in tumour tissue from 14 women with advanced breast cancer. There was no consistent change after EE treatment. MPA tended to decrease ER and PR levels, though some increases were also seen. Responses (10 complete and 3 partial remissions) to sequential cyclical hormono-chemotherapy were not related to ER or PR levels prior to chemotherapy.

Aged↗
PubMed1989

The effect of medroxyprogesterone acetate on aromatase and DNA polymerase alpha activities in breast tumours.

The effect of treatment with the progestogen medroxyprogesterone acetate (MPA) on the peripheral conversion of androstenedione to oestrone and tumour aromatase activity has been examined in post-menopausal women with advanced breast cancer. In addition to being a potent progestational compound, MPA also possesses glucocorticoid properties and glucocorticoids have been shown to stimulate in vitro aromatase activity. While some evidence was obtained of an increase in aromatase activity in tumour tissue after treatment with MPA, peripheral conversion of androstenedione to oestrone was similar when measured before (2.12 +/- 0.67%) and after (1.89 +/- 0.16%) treatment. DNA polymerase alpha activity, measured as a marker of cellular proliferation, decreased from 331 +/- 145 to 156 +/- 93 pmol thymidine triphosphate (TTP)/mg protein per h (P less than 0.02) in tumour samples examined before and after treatment. It is concluded that treatment with high doses of MPA has no effect on the peripheral conversion of androstenedione to oestrone but results in a significant reduction in tumour DNA polymerase alpha activity.

Aged↗
PubMed1989

The effect of breast tumour and normal breast tissue cytosols on oestradiol 17 beta-hydroxysteroid dehydrogenase activity.

We have prepared cytosols of normal breast tissue and breast tumour tissue and examined their effect on 17 beta-oestradiol dehydrogenase (E2DH) activity in cultured normal breast fibroblasts and on the MCF-7 breast cancer cell line. Tumour cytosol increased the activity of E2DH in the reductive (E1----E2) direction in both MCF-7 cells and normal breast fibroblasts. E2DH activity in the oxidative (E2----E1) direction did not change. Increasing the amount of tumour cytosol progressively raised E2DH activity in the E1----E2 direction in MCF-7 cells, whereas equivalent amounts of cytosol from normal tissue had no effect. No change was seen in the oxidative direction. These findings suggest that a factor present in breast tumours may influence E2DH activity and consequently, the hormonal environment and growth of tumours.

17-Hydroxysteroid Dehydrogenases↗
PubMed1989

Relationship between epidermal growth factor and dehydroepiandrosterone and its sulphate in breast cyst fluid.

Gross cystic breast disease is a common condition. Women with apocrine breast cysts may be at higher risk of breast cancer than women with cysts which are lined by flattened epithelium. Apocrine cysts have been shown to be associated with higher intracystic levels of dehydroepiandrosterone sulphate and intracystic sodium to potassium ratios of less than 3. In this study we measured the concentrations of epidermal growth factor, dehydroepiandrosterone and its sulphate in breast cyst fluid. The concentrations of all three analytes were significantly higher in cysts with intracystic Na+/K+ ratios of less than 3 than in cysts with electrolyte ratios of greater than or equal to 3 (P less than 0.001). The higher levels of EGF in cysts with low intracystic electrolyte ratios may provide an explanation of why women with apocrine cysts may be at greater risk of breast cancer. Positive correlations were obtained between concentrations of EGF and DHAS and between EGF and DHA, compatible with the view that intracystic EGF levels may be androgen-modulated. A positive correlation was also obtained between DHA and DHAS concentrations which supports the view that DHA in cyst fluid may be derived from the metabolism of DHAS in the breast cyst wall.

Dehydroepiandrosterone↗
PubMed1989

Diet-induced changes in sex hormone binding globulin and free testosterone in women with normal or polycystic ovaries: correlation with serum insulin and insulin-like growth factor-I.

The purpose of this study was to investigate the effect of calorie restriction on serum concentrations of sex hormone binding globulin (SHBG) in women with normal or polycystic ovaries (PCO) and to examine the possible role of insulin and insulin-like growth factor-I (IGF-I) in mediating changes in SHBG levels. Six normal subjects with mean (SD) body mass index (BMI) 25.5 (2.2) and five subjects with PCO (BMI 36.1 (3.7)) were studied before and after 2 or (PCO only) 4 weeks of a very low calorie diet (330 kcal/day; Cambridge Diet). In both normal women and patients with PCO there was a twofold increase in SHBG concentrations after 2 weeks and this was sustained in the PCO subjects for a further 2 weeks. The rise in SHBG was accompanied by a fall in free testosterone concentrations. There were parallel changes in serum insulin and IGF-I concentrations which decreased during the diet and there were significant negative correlations of SHBG with insulin in both normal subjects (r = -0.62) and women with PCO (r = -0.60). In addition, serum concentrations of an insulin-dependent small molecular weight (34 kDa) binding protein for IGF-I (IGF-BPI) increased significantly during dieting in both groups and were negatively correlated with serum insulin (controls, r = -0.56; PCO, r = -0.68) and positively correlated with serum SHBG levels (controls, r = 0.69; PCO, r = 0.63). In summary, these data indicate that in both normal subjects and those subjects with PCO, calorie restriction results in a highly significant increase in SHBG concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Diet, Reducing↗
PubMed1989

Muscle glycogen storage postexercise: effect of mode of carbohydrate administration.

The primary purpose of this study was to determine whether gastric emptying limits the rate of muscle glycogen storage during the initial 4 h after exercise when a carbohydrate supplement is provided. A secondary purpose was to determine whether liquid (L) and solid (S) carbohydrate (CHO) feedings result in different rates of muscle glycogen storage after exercise. Eight subjects cycled for 2 h on three separate occasions to deplete their muscle glycogen stores. After each exercise bout they received 3 g CHO/kg body wt in L (50% glucose polymer) or S (rice/banana cake) form or by intravenous infusion (I; 20% sterile glucose). The L and S supplements were divided into two equal doses and administered immediately after and 120 min after exercise, whereas the I supplement was administered continuously during the first 235 min of the 240-min recovery period. Blood samples were drawn from an antecubital vein before exercise, during exercise, and throughout recovery. Muscle biopsies were taken from the vastus lateralis immediately after and 120 and 240 min after exercise. Blood glucose and insulin declined during exercise and increased significantly above preexercise levels during recovery in all treatments. The increase in blood glucose during the I treatment, however, was three times greater than during the L or S treatments. The average insulin response of the L treatment (61.7 +/- 4.9 microU/ml) was significantly greater than that of the S treatment (47.5 +/- 4.2 microU/ml) but not that of the I (55.3 +/- 4.5 microU/ml) treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1989

Multiple forms of 17 beta-hydroxysteroid oxidoreductase in human breast tissue.

17 beta-Hydroxysteroid oxidoreductase, the enzyme that catalyses the interconversion of oestradiol and oestrone, is known to be present in human breast tissue. However, it is not known whether one or more forms of the enzyme is present. Homogenates of breast adipose tissue and breast glandular tissue were fractionated and fractions assayed in the oxidative direction with NAD+ and NADP+ as coenzymes, and in the reductive direction with NADH and NADPH as coenzymes. Ultracentrifugation of homogenates showed that there was membrane-bound activity and soluble activity. The soluble activity was due to a number of forms of the enzyme with different molecular weights, three in breast adipose tissue and two in breast glandular tissue, as shown by fractionation with (NH4)2SO4 followed by chromatography on Sephadex G-200. The forms of the enzyme isolated differed in their affinities for substrates and coenzymes and in the relative rates at which they catalysed the oxidative and reductive reactions. Preliminary experiments with breast tumours showed that they also contained membrane-bound activity and more than one soluble form of the enzyme.

17-Hydroxysteroid Dehydrogenases↗