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Biomedical subjects

F Al-Azzawi

Publications and source records attributed to F Al-Azzawi.

At least 37 records · Page 2Linked to original sources

Oestrogen receptor beta is not present in the pilosebaceous unit of red deer skin during the non-breeding season.

Androgens and oestrogens both have roles in skin physiology. Recently a second oestrogen receptor (ERbeta) has been identified in androgen-dependent tissues. The red deer grows a breeding season, androgen-dependent mane when plasma testosterone rises; this is replaced with small neck hairs during the non-breeding season. In non-breeding season deer skin, ERbeta was localised to the blood vessels and arrector pili muscle, but in contrast to human skin, not in the pilosebaceous unit or epidermis. The androgen receptor was not expressed. Further studies with breeding season skin may help to elucidate whether serum androgens or androgen receptor expression can modulate the expression of ERbeta in skin.

Animals↗

Immunolocalisation of oestrogen receptor beta in human tissues.

Oestrogens exert their actions via specific nuclear protein receptors that are members of the steroid/thyroid receptor superfamily of transcription factors. Recently, a second oestrogen receptor (ERbeta) has been cloned, and using reverse transcription-PCR and immunohistochemistry it has been shown to have a wide tissue distribution in the rat that is distinct from the classical oestrogen receptor, ERalpha. Using commercial polyclonal antisera against peptides specific to human ERbeta, we have determined the sites of ERbeta expression in archival and formalin-fixed human tissue and compared its expression with that of ERalpha. ERbeta was localised to the cell nuclei of a wide range of normal adult human tissues including ovary, Fallopian tube, uterus, lung, kidney, brain, heart, prostate and testis. In the ovary, ERbeta was present in multiple cell types including granulosa cells in small, medium and large follicles, theca and corpora lutea, whereas ERalpha was weakly expressed in the nuclei of granulosa cells, but not in the theca nor in the copora lutea. In the endometrium, both ERalpha and ERbeta were observed in luminal epithelial cells and in the nuclei of stromal cells but, significantly, ERbeta was weak or absent from endometrial glandular epithelia. Epithelial cells in most male tissues including the prostate, the urothelium and muscle layers of the bladder, and Sertoli cells in the testis, were also immunopositive for ERbeta. Significant ERbeta immunoreactivity was detected in most areas of the brain, with the exception of the hippocampus - a tissue that stained positively for ERalpha. In conclusion, the almost ubiquitous immunohistochemical localisation of ERbeta indicates that ERbeta may play a major role in the mediation of oestrogen action. The differential expression of ERalpha and ERbeta in some of these tissues suggests a more complex control mechanism in oestrogenic potential than originally envisioned.

Adult↗

Identification of a cycle-modulated 200-kDa endometrial antigen by a monoclonal antibody LDS60.

We have developed a mouse monoclonal antibody, LDS60, against a cycle-dependent antigen by immunising (MF1 x BALB/c)F1 mice with a human endometrial membrane preparation. In formalin fixed paraffin embedded sections, LDS60 identified an epithelial specific antigen which exhibited a specific pattern of expression during the menstrual cycle. It was only occasionally expressed during the proliferative phase. During the early-secretory phase, there was intracytoplasmic staining in about half of the glands examined. This was in the form of small microvesicles, either near the base of the cell or supranuclear. In the mid-secretory phase the same proportion of glands exhibited staining in the form of micro-vesicles that were noted to accumulate nearer to the cell apices. In the late-secretory phase, there was no intracytoplasmic staining and the antigen was localised to the luminal border of the glandular epithelium and some staining appeared within the gland lumen of approximately 20% of glands. It is also diffusely expressed in some mucous secreting cells in the tongue, stomach and colon, as well as lung pneumocytes. The antigen has a molecular weight of approximately 200 kDa as identified by immunoblotting. This antigen exhibits similarities to MUC-1 which is involved in uterine receptivity and could therefore have a similar role. Its cycle modulation suggests that it could be used to monitor the uterine response to steroids.

Animals↗

Continuous combined hormone replacement therapy compared with tibolone.

OBJECTIVE: To compare relief of vasomotor symptoms, changes in lipoproteins, and bleeding patterns in postmenopausal women receiving either continuous combined hormone replacement therapy (HRT) of estradiol valerate and norethisterone or tibolone 2.5 mg/day. METHODS: In a multicenter, randomized, open-label study, 235 postmenopausal women received one of the above-mentioned treatments. Fasting lipoproteins were measured at baseline and at 3, 6, and 12 months. At each visit, participants completed Greene climacteric questionnaires and recorded any bleeding episodes. Data are presented as mean +/- standard deviation if normally distributed, median and interquartile range if non-normally distributed, or as frequency count. For menopausal symptoms and diary card data, the differences were tested by Wilcoxon rank-sum test. RESULTS: One hundred sixteen women received continuous combined HRT and 119 women received tibolone; 72 and 76 women, respectively, completed 12 months of therapy. Both treatments effectively relieved vasomotor symptoms and reduced serum total cholesterol. Continuous combined HRT, but not tibolone, significantly reduced low-density lipoprotein levels. Both treatments reduced high-density lipoprotein levels, but the effect was more profound with tibolone. The initial bleeding score was higher for women taking continuous combined HRT; however, by the end of the study, the percentages of amenorrheal women were comparable. Endometrial histology was similar for both treatments at the end of the study, although two cases of proliferative endometrium were found in the tibolone group. CONCLUSION: Estradiol valerate-norethisterone continuous combined HRT controls symptoms and is associated with a safe lipid profile.

Climacteric↗

Endometrial histomorphometry of trimegestone-based sequential hormone replacement therapy: a weighted comparison with the endometrium of the natural cycle.

Histomorphometric changes in the endometrium were evaluated under the effect of a trimegestone-based sequential hormone replacement therapy (HRT) regimen, and the findings were compared to those in endometrium of the natural cycle. Endometrial samples were taken from postmenopausal women who completed a randomized, double blind, dose-ranging study of oral trimegestone (0.05, 0.1, 0.25 and 0.5 mg per day) from day 15 to day 28 with continuous micronized oestradiol 2 mg daily for six treatment cycles. The HRT-treated endometrium, irrespective of the dose, had a smaller mean total glandular area, smaller average glandular diameter, smaller mean total vascular space area and diameter than the luteal phase. Stromal cellularity was similar in the four dose groups. There were reduced glandular secretions in the endometrium from the high dose group. The relative weighting of these histological parameters was evaluated by linear discriminant analysis. The weighted values were dose independent, and may therefore represent either a specific effect of trimegestone, number of days administered, or both. We have constructed an equation to assign a value for a histological parameter which determines the position on linear discriminant functions. These assigned values can be used in other sequential HRT regimens to determine the relative influence of a given progestogen on endometrial morphology in relation to different phases of the natural cycle.

Aged↗

The effect of hormone replacement therapy on the number and the proliferation index of endometrial leukocytes.

This study aimed to determine the changes in endometrial leukocyte subpopulations under sequential hormone replacement therapy (HRT) during the late progestogenic phase. The number of leukocytes was determined using immunohistochemistry utilizing monoclonal antibodies to CD45 (total leukocytes), CD56 (endometrial granulated lymphocytes), CD3 (T-cells), and CD68 (macrophages). Leukocyte proliferation was demonstrated using in-situ hybridization with a histone probe, and the proliferation index was determined using double labelling for Ki67 (Mib1). Compared to the corresponding phase of the physiological cycle, sequential HRT-treated endometrium exhibited a 95% increase in CD45(+) cells (P < 0.05), a 130% increase in CD56(+) cells (P < 0.05), and a 113% increase in CD3 cells. There was a non-statistically significant drop in the number of CD68(+) cells. The number of proliferating leukocytes increased in sequential HRT endometrium.

Antibodies, Monoclonal↗

Acceptability and patterns of uterine bleeding in sequential trimegestone-based hormone replacement therapy: a dose-ranging study.

Trimegestone is a norpregnane progestogen which is being developed in combination with oral oestradiol as postmenopausal hormone replacement therapy (HRT). In this multicentre dose-ranging study using randomized parallel groups, four doses of trimegestone were used to compare data on the patterns of uterine bleeding, the endometrial histology, and the control of menopausal symptoms in 203 women who completed treatment for 6 months. The treatment consisted of micronized oestradiol (2 mg/day) and one of four doses of trimegestone, which was administered sequentially for days 15-28 of the treatment cycle. Higher doses of trimegestone were associated with later onset of bleeding, which was lighter and of shorter duration than that observed with lower doses. The variability of the day of onset of bleeding in individual women was greater when bleeding occurred before the end of the progestogen phase (early bleeders) than when it occurred afterwards (late bleeders). All women enrolled in the study experienced good control of menopausal symptoms, with minimal progestogenic adverse effects, there being no statistically significant difference between the four dose groups.

Aged↗

The distribution of endometrial leukocytes and their proliferation markers in trimegestone-treated postmenopausal women compared to the endometrium of the natural cycle: a dose-ranging study.

The effect of trimegestone-based sequential hormone replacement therapy (HRT) on the distribution of endometrial leukocytes and Ki-67 expression was investigated and the findings compared with the endometrium of the natural cycle. Endometrial cells positive for CD45(+), CD56(+), CD3(+), Ki-67(+) and CD45(+)/Ki-67(+) antigens were immunohistochemically evaluated in samples from postmenopausal women who completed a randomized, double-blind, dose-ranging study of oral trimegestone (0.05, 0.1, 0.25 and 0.5 mg per day) from days 15 to 28 with continuous micronized oestradiol 2 mg daily for six treatment cycles. The control samples were luteinizing hormone (LH)-dated endometrial biopsies. Cell counts were interpreted using linear discriminant analysis and unpaired t-test. The dose of trimegestone did not significantly affect the mean count of CD45(+), CD56(+), CD3(+), Ki-67(+) and CD45(+)/Ki-67(+) cells in the endometrial biopsies obtained from treated women. Endometrial sections from women who bled on the day of the biopsy contained higher numbers of CD45(+) and CD56 cells. In the trimegestone-treated endometrium, CD45(+), CD56(+) and CD3(+) cell expression was similar to the proliferative and early secretory phases of the natural cycle. However the expression Ki-67 and CD45(+)/Ki-67(+) cells was similar to the menstrual phase of the natural cycle endometrium. Women treated with four doses of trimegestone exhibited four different bleeding patterns. Therefore the endometrial infiltration with these cells did not explain the pattern of bleeding in women on this HRT regimen.

Aged↗

Sex hormone status and bone metabolism in men with Crohn's disease.

BACKGROUND: Men with Crohn's disease (CD) are at risk of osteoporosis, but the factors contributing to low bone mineral density and its optimum treatment have not been established. AIM: To investigate the sex hormone status of men with CD, and to establish the influence of sex hormones on their bone metabolism. METHODS: Bone density was measured by dual energy X-ray absorptiometry at the hip and lumbar spine in 48 men with CD. Total serum testosterone and gonadotrophins were measured in all subjects and the free androgen index calculated in men with low or borderline total testosterone. Serum osteocalcin, pro-collagen carboxy-terminal peptide, bone specific alkaline phosphatase and urinary deoxypyridinoline were measured as markers of bone turnover. RESULTS: Eight (17%) men had osteoporosis, and a further 14 (29%) had osteopenia. Three (6%) men had a low free androgen index and normal gonadotrophins consistent with secondary hypogonadism, two of whom had osteopenia of the hip and spine. Age (P = 0.002) and small bowel Crohn's disease (P = 0.02) were the only independent predictors of serum testosterone. There was a significant association between total testosterone and osteocalcin (r = 0.53, 95%, CI: 0.29-0.71, P = 0.0001) which was independent of age and current steroid use (P = 0.0001). CONCLUSIONS: Previously undiagnosed hypogonadism is an uncommon cause of low bone density in men with CD. The independent association between testosterone and the bone formation marker osteocalcin suggests sex hormone status influences bone metabolism in men with CD. The results suggest testosterone replacement might be effective treatment for some men with osteoporosis and Crohn's disease.

Absorptiometry, Photon↗

Increased bone resorption in patients with Crohn's disease.

BACKGROUND: Patients with Crohn's disease are at risk of osteoporosis and premature fracture. However, the pathophysiology underlying bone loss remains poorly understood and the optimum treatment has not been established. AIM: To investigate mechanisms of bone loss in Crohn's disease using biochemical markers of bone turnover. METHODS: Bone mineral density was measured at the hip and spine using dual-energy X-ray absorptiometry in 117 patients (48 male) with Crohn's disease. Bone turnover was assessed by measuring serum osteocalcin (BGP), pro-collagen carboxy-terminal propeptide (PICP), bone specific alkaline phosphatase (BALP) and urinary deoxypyridinoline (DPD); and compared to age-matched healthy controls (n = 28). RESULTS: Bone mineral density was reduced (z-score < -1) in 48 (41%) patients with Crohn's disease. Mean values for bone formation markers in patients with Crohn's disease were all within the normal reference range (BGP 8.92 (+/- 3.23) ng/mL (normal range 3.4-10.0), BALP 17.6 (+/- 12.6) U/L (normal range 11.6-43.3), PICP 95.1 (+/- 46.5) ng/mL (normal range 69-163)) and were not significantly different to the control population. However, mean urinary DPD was significantly higher in patients with Crohn's disease compared to healthy controls (10.97 (+/- 9.22) nM DPD/mM creatinine vs. 5.02 (+/- 1.03) nM DPD/mM creatinine, difference in means = 5.95, 95% CI: -9.6 to -2.3, P = 0.00001) and compared to the UK reference range DPD levels were increased in 74 (63%) patients. CONCLUSIONS: Bone resorption as evidenced by urinary DPD was frequently increased in patients with Crohn's disease and was significantly higher than in an age-matched control population. The high levels of urinary DPD suggest increased bone collagen degradation may contribute to osteoporosis in patients with Crohn's disease. These results suggest anti-resorptive agents such as the bisphosphonates may be effective treatment for osteoporosis in Crohn's disease.

Adult↗

The effect of oestrogen on intimal hyperplasia in cultured human ovarian veins.

The beneficial effect of oestrogen on blood vessels may include modulation of vascular response to injury. In this experiment we set out to develop an in-vitro model, using all human materials, for the study of vascular changes in culture, and their response to oestrogen treatment. Human ovarian vein segments were obtained from 15 hysterectomy specimens, and cultured with and without the addition of 17beta-oestradiol. Paired control veins were cultured with the inert 17alpha-oestradiol. The veins were stained with anti-alpha-smooth muscle actin and Miller's elastin, and intimal thickness measured. Cultured veins developed a significant degree of intimal thickening [15.7 versus 8.25 microm in fresh veins, 95% confidence intervals (CI) 13.6, 17.8 and 6.3, 10.2 respectively; P = 0.0001]. The addition of 17beta-oestradiol, but not 17alpha-oestradiol, led to a significant reduction in intimal hyperplasia (intimal thickness 8.85 microm; 95% CI 6.9, 10.8; P = 0.008). The mean number of nuclei per high-power field was also significantly lower in the intima of oestrogen-treated compared to untreated veins (11.6; 95% CI 9.9, 13.26 versus 14.05; 95% CI 12.5, 15.6; P = 0.001). Our data suggest that intimal hyperplasia in cultured ovarian veins is effectively reduced by oestrogen.

Cell Division↗

Endometrial responses to hormone replacement therapy: histological features compared with those of late luteal phase endometrium.

We evaluated the histological features of the endometrium in relation to the bleeding pattern in a group of women receiving oral cyclical combined hormone replacement therapy (HRT), and compared the histological features with those of luteinizing hormone (LH)-dated endometrial biopsies obtained from healthy women at the time of sterilization. A total of 103 women completed 6 months of HRT therapy. All received a regimen of 2 mg oestradiol valerate daily, with 1 mg norethisterone added for the last 12 days of every 28-day cycle. Endometrial biopsies were scheduled for the end of the study (days 27-29 of the last cycle of therapy). Using the classical histological criteria, secretory endometrial changes were demonstrated in the majority (n = 89) of cases. The remaining were insufficient or inactive (n = 12), proliferative (n = 1) or atrophic (n = 1). Forty-nine women had a mean cycle length of less than 29 days (early bleeders), 50 women experienced cycles of more than 29 days (late bleeders) and four did not experience any bleeding. When the individual histological structures were examined, using image analysis, there were no statistically significant differences in the histological features when the long cycles in early bleeders were compared with those in late bleeders. LH-dated endometrium showed a high degree of homogeneity that was consistent with cycle day as described by the classic criteria, but HRT-treated endometrium exhibited a wide range of variability. HRT-treated endometrium from the subset of women who bled on or after day 29, and whose biopsies were obtained before the onset of bleeding, differed significantly from the endometrium taken at the corresponding phase of the physiological cycle. We conclude that the use of classical histological criteria, which are used in relation to the physiological cycle, in the study of HRT-treated endometria is inappropriate.

Endometrium↗

Sexual interest in postmenopausal women is related to 5alpha-reductase activity.

Many studies to date have suggested a role for testosterone in women's interest in sex after the menopause. However, this does not appear to be related to serum concentrations of testosterone. Testosterone is converted to the more active dihydrotestosterone by an enzyme, 5alpha-reductase, found in target tissues. The activity of this enzyme has been shown to be variable, being more active in women with hirsutism and men with benign prostatic hypertrophy than in normal controls. We have shown that women complaining of a loss of interest in sex after the menopause have higher amounts of 5alpha-reductase activity, as reflected by urinary ratios of the 5alpha-product (androsterone) to the 5beta-product (aetiocholanolone) of androstenedione, than women with no loss of interest in sex after the menopause. However, of those women who noted a loss of interest in sex after the menopause, the women who responded to oestrogen replacement had higher amounts of 5alpha-reductase activity than those whose interest in sex did not improve with oestrogen replacement. The urinary aetiocholanolone:androsterone ratio may be predictive of which women will experience a loss of interest in sex following the menopause (natural or induced) and which of these women will respond to oestrogen replacement.

Adult↗

An investigation of maternal morbidity with identification of life-threatening 'near miss' episodes.

This study was designed to investigate the pattern of obstetric morbidity and to determine the frequency of serious life-threatening episodes as a basis for clinical audit. The records of over 2,000 maternities from a National Health Service Consultant Unit during a six-month period were analysed. Morbidity was noted in almost a quarter of the cases, and life-threatening episodes, termed 'near miss' morbidity, were identified. As the maternal death rate has fallen in this country, maternal morbidity has come to represent a more useful indicator of obstetric care than mortality. The results of this study identify the need for an agreed set of definitions for 'near miss' morbidity, and suggest that not only should it be included for discussion in unit perinatal meetings, but that Regional obstetric morbidity enquiries would provide valuable denominator data on morbidity.

Female↗

Blood coagulation profile in long-term hormone replacement therapy with mestranol.

The coagulation profile of oophorectomised women on long-term (15 yr) hormone replacement therapy with mestranol (30 micrograms/day) is compared to that of women on long-term placebo. Analysis of these data showed no significant difference in prothrombin time, partial thromboplastin time or in anti-thrombin III level in these groups.

Adult↗

Differential effect of long-term oestrogen therapy on trabecular and cortical bone.

The effect of long-term oestrogen therapy has been assessed in 40 oophorectomised women. Twenty-one of the women had received mestranol (mean 26 micrograms/day) and 19 received placebo tablets for a mean duration of 14 yr. A newly developed gamma-ray computed tomography (CT) scanner was used to measure trabecular and cortical bone separately in the distal radius. Bone density in the lumbar spine was measured using dual photon absorptiometry (DPA). Prevention against bone loss was demonstrated at all sites for the mestranol treated group (P less than 0.01). The deficit of radial trabecular bone (27%) was greater than that for radical cortical bone (14%). The deficit for the spine was intermediate (20%). One-year follow-up radial measurements showed a significant 1.2% increase (P less than 0.01) in cortical bone for the treated group. The DPA measurement was found to be best correlated (r = 0.80) with a mixed trabecular and cortical bone parameter in the radius. We conclude that the degree of bone loss at any site is dependent on the proportion of trabecular bone present.

Aged↗

Lipoprotein and apolipoprotein levels in postmenopausal women on continuous oestrogen/progestogen therapy.

Levels of serum lipoproteins and apolipoproteins were monitored for 48 weeks in two groups of women taking part in a double-blind trial of continuous oestrogen/progestogen with and without oestriol. There were no differences between the effects of the two treatments on the substances measured. Triglycerides did not change and there was a transient fall in very low density lipoprotein cholesterol. Low density lipoprotein cholesterol fell over the first 24 weeks but rose thereafter to pretreatment levels. There was a decrease in high density lipoprotein (HDL) cholesterol due to a transient fall in HDL2 cholesterol and a gradual decrease in HDL3 cholesterol. Consequently, the only change in lipid levels present after 48 weeks was a decrease in HDL3 cholesterol, the clinical significance of which is uncertain. There was, however, an increase in apoprotein B levels and decreases in apoprotein AI and AII levels. These alterations in apoprotein levels may be unfavourable, since apoprotein B levels have been positively correlated and apoprotein AI and AII levels negatively correlated with coronary heart disease.

Apolipoproteins↗