PubMed Health⌕ Search

Biomedical subjects

F Al-Azzawi

Publications and source records attributed to F Al-Azzawi.

At least 19 recordsLinked to original sources
PubMed2006

Trimegestone differentially modulates the expression of matrix metalloproteinases in the endometrial stromal cell.

Matrix metalloproteinases (MMP) are considered to be of critical importance in the initiation of menstruation where MMP protein levels are reciprocally modulated by the actions of the gonadal steroid hormones, estradiol (E(2)) and progesterone (P4), with P4 being considered the principal suppressor of endometrial MMP expression. Trimegestone (T) is a novel progestagen that tightly controls menstruation timing and duration through mechanisms that might involve MMP suppression. Endometrial stromal cells treated with 10(-6) M E(2), P4 or T in the presence and absence of 10(-6)M RU486 showed that both T and P4 suppressed the expression of MMP-1 and MMP-3 transcripts and secreted protein, whereas MMP-9 was not produced in culture. The suppressive effect of T or P4 on MMP-1 and MMP-3 transcript levels was enhanced in the presence of E(2) and attenuated in the presence of RU486, although MMP-1 proteins were unaffected by the presence of RU486, which alone acted as a partial progesterone agonist in these cultures. Immunohistochemistry with MMP-1, MMP-3 and MMP-9-specific antibodies performed on endometrial biopsies obtained from non-treated, LH-dated, normally cycling women and endometrial biopsies obtained from postmenopausal women treated with T-based HRT showed that immunoreactive MMP-1 and MMP-3 was higher in the menstrual phase, whilst MMP-9 expression was higher in the late luteal phase (P = 0.03) and T significantly inhibited the presence of MMP-9(+) cells. These data suggest that T acts in a similar manner to P4, but causes subtle differences in expression patterns of MMPs that may explain the different clinical effect that this progestagen has on endometrial behaviour compared to P4.

Adult↗
PubMed2004

Randomized trial of effects of estradiol in combination with either norethisterone acetate or trimegestone on lipids and lipoproteins in postmenopausal women.

OBJECTIVE: This double-blind, randomized, multicenter study was designed to compare the blood lipid profiles in postmenopausal women after treatment with either a combined formulation containing estradiol (2 mg) and trimegestone (TMG 0.25 or 0.5 mg) or a standard hormone therapy (HT) containing estradiol and norethisterone acetate. METHOD: The serum concentrations of several lipids and lipoproteins were measured in this study, which was conducted over 13 cycles, each of 28 days. A total of 487 subjects were included, 349 of whom completed the study. RESULTS: The circulating concentrations of high density lipoprotein (HDL) cholesterol, HDL2 cholesterol and apolipoprotein (apo) AI increased from baseline in both estradiol/trimegestone groups, whilst levels of HDL3 cholesterol were unchanged. In contrast, in the estradiol/norethisterone acetate group, HDL cholesterol, HDL3 cholesterol and apo AI concentrations were reduced from baseline, while HDL2 cholesterol remained unchanged. Total cholesterol, low density lipoprotein (LDL) cholesterol, lipoprotein(a) and apo-B concentrations were reduced in all treatment groups. The concentration of triglycerides was elevated after treatment with the estradiol/trimegestone combinations but was unchanged after treatment with the estradiol/norethisterone acetate combination. The differences in the lipid pattern between the groups may be explained by the different pharmacological properties of the two progestogens: norethisterone exerts an androgenic effect and opposes the estrogen-induced increase in HDL cholesterol, whilst trimegestone has no androgenic effect and does not oppose the estrogenic effect. CONCLUSION: Overall, the results of this study suggest that the use of trimegestone in combination with estradiol may be preferable to norethisterone acetate because of the more favorable HDL and apo AI profile.

Apolipoproteins↗
PubMed2004

Nasal physiological changes during pregnancy.

Rhinitis in pregnancy has been previously investigated with variable results. This study examines all the variables of the nasal airway simultaneously for the first time. Eighteen women were recruited in the first trimester of pregnancy and followed through to the postpartum period to monitor the changes that occurred. Measurements of the nasal airway included anterior rhinoscopy (AnR), peak inspiratory nasal flow, acoustic rhinometry, anterior rhinomanometry (ARM), and the saccharin test with rhinitis questionnaire scores providing a symptomatic measurement. All the tests showed a trend consistent with decreasing nasal patency when expressed as an average for the group as a whole, although only AnR, ARM, mucociliary clearance time and rhinitis questionnaire scores were statistically significant (P < or = 0.05). This confirms the effect of pregnancy on the nasal mucosa and coincides with the rise in the serum concentration of the female sex hormones with gestational age, returning to normal postpartum. Pharmacological antagonism of oestrogens may therefore relieve nasal congestion and is currently under further research.

Airway Resistance↗
PubMed2003

Oestrogen receptor beta is the predominant oestrogen receptor in human scalp skin.

Oestrogens play a major role in non-classic target tissues in both sexes, yet there have been few studies on estrogens and skin. Recently a second oestrogen receptor (ERbeta) has been discovered. Therefore, we have compared the expression of oestrogen receptor alpha (ERalpha), beta (ERbeta), the androgen receptor (AR) and a cell proliferation marker in male and female non-balding scalp skin. ERbeta was the major steroid receptor expressed in human skin. It was highly expressed in epidermis, blood vessels and dermal fibroblasts, in contrast to ERalpha and AR. In the hair follicle, ERbeta expression was localized to nuclei of outer root sheath, epithelial matrix and dermal papilla cells, in contrast to ERalpha, and the AR, which was only expressed in dermal papilla cells. Serial sections also showed strong nuclear expression of ERbeta in the cells of the bulge, while neither ERalpha nor AR was expressed. In the sebaceous gland, ERbeta was expressed in both basal and partially differentiated sebocytes. ERalpha exhibited a similar pattern of expression, while the AR was expressed in the basal and very early differentiated sebocytes. There was no obvious difference in the expression of either oestrogen receptor in male or female skin. The wide distribution of ERbeta in human skin suggests that oestrogens may play an important role in the maintenance of skin and in the regulation of the pilosebaceous unit, and provides further evidence for oestrogen action in non-classic target tissues. The differential expression of ERalpha, ERbeta and AR in human skin suggests that the mechanisms by which steroid hormones mediate their effects may be more complex than previously thought.

Aged↗
PubMed2003

Comparison of a novel vaginal ring delivering estradiol acetate versus oral estradiol for relief of vasomotor menopausal symptoms.

OBJECTIVE: To compare a novel vaginal ring releasing estradiol acetate (Menoring; Galen Holdings) with oral estradiol for relief of moderate to severe vasomotor symptoms in healthy postmenopausal women. DESIGN: This was a prospective, double-blind, multicenter, randomized, parallel-group study. METHOD: Women (n = 159) aged < 65 years experiencing >or= 20 hot flushes/night sweats per week received either a vaginal ring releasing estradiol acetate at a rate equivalent to 50 microg/day estradiol plus placebo tablets or oral estradiol 1 mg/day plus a placebo vaginal ring for 24 weeks. For patients with inadequate control of symptoms, the dosage was doubled at 12 weeks. A 24-week, open-label extension of the vaginal ring treatment followed double-blind treatment. RESULTS: The frequency of hot flushes/night sweats was significantly reduced (p < 0.001) in both groups at 12 and 24 weeks from baseline, by 84% and 94% for the vaginal ring group and by 73% and 83% for the oral group, respectively. The mean intensity of urogenital symptoms decreased from screening to the end of treatment in both groups. The incidence of adverse events was similar for both groups. No clinically relevant local effects of the vaginal ring were observed. CONCLUSIONS: The vaginal ring relieved both systemic and urogenital symptoms and was well tolerated and accepted. Overall, the efficacy, safety and acceptability of the vaginal ring were comparable with those of oral estradiol therapy.

Administration, Intravaginal↗
PubMed2003

Meningioma and hormonal influences.

Meningiomas are slow-growing benign brain tumors. The etiology of meningioma is largely unknown, and exposure to high-dose ionizing radiation and coexistence with certain rare genetic conditions explain only a small fraction of the incidence of the disease. The evidence that implicates gender-specific hormones in the pathogenesis of meningioma emanates from data showing increased growth of meningiomas during pregnancy and change in size during menses. Observational data have identified the menopause and oophorectomy as conferring protection against the risk of developing meningiomas, while adiposity is positively associated with the disease. These tumors are also positively associated with breast cancer, although they express a different gonadal steroid receptor repertoire. About 70% of meningiomas express progesterone receptors, while fewer than 31% express estrogen receptors. These observations suggest that progesterone influences tumor growth. A progesterone antagonist such as mifepristone therefore may inhibit tumor growth. The use of hormone replacement therapy in symptomatic postmenopausal women either with previously treated disease or with dormant tumors is discussed, but remains controversial.

Breast Neoplasms↗
PubMed2002

Pulsed estrogen therapy: from cellular mode of action to tissue effects.

Failure to achieve a uniform response to estrogen replacement therapy may be related to the dose or route of administration of estrogen. The established doctrines of estrogen replacement therapy are under scrutiny. Recent discoveries have prompted a complete re-evaluation of estrogen action at the biochemical, physiological, and molecular level. Further questions remain as regards the correct dose of estrogen. It is becoming clear that individual cell types respond differently to different doses of estrogen and, even within a single experimental system, a considerable variation in response can be seen. Furthermore, there is an evident link between the duration of exposure to estradiol (continuous versus pulsed) and cellular behavior. In addition to this, it appears that ligand binding has a significant effect on estrogen receptor dynamics. The concept of pulsed estrogen therapy has recently been exploited by the introduction of a nasal spray delivery system. The administration of estradiol via the nasal mucosa is made possible by the use of randomly methylated alpha-cyclodextrin (RAMEB), a beta-cyclodextrin which increases the solubility of estradiol. The original pulsed plasma concentration time profile of E2 following transnasal administration was studied and the results were compared with orally or transdermally administered E2. Being dose-proportional, estradiol transnasally administered at a dose of 300 microg gave an estimated 24-h systemic exposure to exogenous estradiol (area under the curve) close to that of reference treatments. It would appear that pulsed estrogen therapy has a different cellular mechanism to that of traditional forms of administration. This new concept provides reliable dose-dependent exposure to estradiol, avoids the hepatic first-pass effect and demonstrates good biological and clinical efficacy. This development, linked to our improved understanding of the cellular effects of estrogen, ushers in a new era in postmenopausal hormone replacement therapy.

Administration, Cutaneous↗
PubMed2001

Specific inhibition of estrogen receptor alpha function by antisense oligodeoxyribonucleotides.

We have tested the effect of a range of antisense oligodeoxyribonucleotides (ODN) directed against the human estrogen receptor alpha (ERalpha) on ERalpha protein expression and function. Antisense ERalpha ODN transfected into the ERalpha-positive human breast carcinoma cell line MCF7-K2 showed variable responses dependent on the oligo used. The most active antisense ODN (oligo 7) decreased the levels of ERa protein by 61% as measured by Western blot analysis. Exogenous 17beta-estradiol (17beta-E2), but not 17alpha-E2, augmented this effect, with a threshold effect at 10(-8) M 17beta-E2. The inhibitory effect of antisense ERa oligo 7 was confirmed by measurement of functional ERalpha protein. 3H-17beta-E2 binding to MCF7 cell extracts was inhibited to approximately 40% of control values in the presence of oligo 7. Antisense-transfected MCF7-K2 cell cultures produced a further 30% binding reduction in the presence of exogenous 17beta-E2. An inhibitory effect on 17beta-E2-dependent cell function was confirmed by the demonstration that ERalpha oligo 7-transfected MCF7-K2 cells failed to exhibit 17beta-E2-stimulated cell proliferation. Exogenous 17beta-E2 enhanced the inhibitory effect of the antisense ODN by increasing ODN transfection efficiency but without ERalpha catabolism via the proteosomal pathway, suggesting an effect of 17beta-E2 on the plasma membrane and the existence of different ERalpha degradation pathways in the MCF7-K2 cell subclone. As 17beta-E2 had no effect on ERalpha protein degradation, we conclude that the observed reduction of ERalpha protein levels is due solely to the presence of the antisense ERalpha ODN. Antisense ERalpha ODN molecules, therefore, may form the basis of effective therapies against ERalpha-dependent malignancies.

Adenocarcinoma↗
PubMed2001

Trimegestone: expanding therapeutic choices for the treatment of the menopause.

UNLABELLED: Trimegestone is a novel norpregnane progestin, which has a potent progesterone receptor and very low androgen receptor affinities but no detectable affinity to oestrogen receptor. Trimegestone has been developed for use in conjunction with oestrogen for postmenopausal hormone replacement therapy (HRT). The dose of trimegestone required for endometrial safety was optimised in a dose ranging study. Oral trimegestone was administered at 0.05, 0.1, 0.25 and 0.5 mg/day, days 15 - 28 along with continuous oral micronised oestradiol at 2 mg daily. The majority of women in the four dose groups experienced relief of climacteric symptoms by the end of the third treatment cycle. The incidence of pre-menstrual tension-like symptoms was low and did not differ between the four dose groups. After 6 months of treatment, the bleeding pattern showed a clear dose-dependent modulation such that the higher the dose of trimegestone administered the more predictable was the day of onset of bleeding and the shorter and lighter the bleeding episodes became. This was further confirmed in another study comparing trimegestone in 0.5 and 0.25 mg doses to norethisterone acetate, where women on the 0.5 mg dose experienced more favourable bleeding pattern compared with the lower dose of 0.25 mg or to norethisterone acetate. In the dose ranging study, 96% of endometrial specimens obtained at the end of the study had secretory changes. The lipoprotein profile measured at baseline, 3 and 6 months during the dose ranging study confirmed the fact that trimegestone, irrespective of the dose, did not negate the beneficial effects of oestrogen on lipids. CONCLUSION: trimegestone is an effective and well-tolerated new progestin, which does not negate the beneficial effects of oestrogen on lipids.

Female↗
PubMed2001

Changes in serum vascular endothelial growth factor following initiation of estrogen replacement after hysterectomy and oophorectomy.

BACKGROUND: Vascular endothelial growth factor has been shown to play an important role in preservation and restoration of endothelial integrity. Similar effects on endothelial function have been described with estrogen replacement. This poses the question whether some of the mechanisms ascribed to estrogen are in fact vascular endothelial growth factor mediated. The objective of this study was to examine the effect of continuous transdermal estrogen replacement on serum levels of secreted vascular endothelial growth factor in women following hysterectomy and oophorectomy. METHODS: In a nonrandomized, prospective study, 40 hysterectomized and oophorectomized women were treated with transdermal estrogen. Their serum vascular endothelial growth factor levels were measured before and six months following estrogen treatment, using a commercially available ELISA kit. RESULTS: The mean serum vascular endothelial growth factor level fell from 328 ng/ml (s.d. 164) before treatment to 285 ng/ml (s.d. 124) following six months of estrogen replacement. This decrease was statistically significant (p<0.03). CONCLUSION: Transdermal estrogen replacement in hysterectomized and oophorectomized women appears to be associated with a significant reduction in secreted serum vascular endothelial growth factor. However, the effect of hysterectomy and oophorectomy per se needs to be explained in appropriately designed trials.

Administration, Cutaneous↗
PubMed2000

Endometrial protection from tamoxifen-stimulated changes by a levonorgestrel-releasing intrauterine system: a randomised controlled trial.

INTRODUCTION: Tamoxifen is currently the most commonly used adjuvant treatment for breast cancer, however, it frequently causes episodes of unscheduled uterine bleeding, which could be associated with proliferative changes of the endometrium, or even endometrial cancer. We aimed to assess whether a levonorgestrel intrauterine system could modulate the uterine responses to tamoxifen. We also aimed to assess women's tolerance of the screening procedures, the insertion, removal, and potential side-effects of the device. METHODS: We did a randomised controlled trial, in which postmenopausal women who had had at least 1 year of adjuvant tamoxifen treatment and who were undergoing regular follow-up for breast cancer were randomly assigned to either endometrial surveillance alone, or endometrial surveillance before and after insertion of the levonorgestrel intrauterine system for 12 months. We assessed tolerance of the surveillance procedures and the device with visual analogue scales. FINDINGS: Baseline assessment showed only benign uterine changes in all women (n=122). Hysteroscopic assessment indicated a uniform decidual response (confirmed histologically in 40 of 41 cases) in all women fitted with the intrauterine system; there were no new polyps in these women and 13% had fewer fibroids than in controls. Both screening procedures and device were well tolerated. There was an excess of bleeding in the women fitted with intrauterine systems but this resolved to a baseline similar to those receiving surveillance only. INTERPRETATION: The levonorgestrel-releasing intrauterine system had a protective action against the uterine effects of tamoxifen. The effectiveness of this device in preventing uterine changes in the endometrium needs to be assessed in the context of decreasing the need for repeated investigations of postmenopausal bleeding in women taking tamoxifen.

Aged↗
PubMed2000

The effect of hormone replacement therapy on the immunoreactive concentrations in the endometrium of oestrogen and progesterone receptor, heat shock protein 27, and human beta-lactoglobulin.

We determined the expression of oestrogen receptor (ER), progesterone receptor (PR), heat shock protein 27 (HSP27) and human beta-lactoglobulin in the endometrium under hormone replacement therapy (HRT). The immunohistochemical expression during the late progestogenic phase of sequential HRT was compared semi-quantitatively and using image analysis, to the early, mid-, and late luteal phase of the physiological cycle. Under sequential HRT, smaller glands were positive for the ER but larger glands with more advanced secretory features were negative. ER expression was lower in the stroma under HRT, and the difference was statistically significant compared with the early luteal phase (P < 0.05). Expression of HSP27 under HRT was lower in the epithelium but higher in the stroma compared with the physiological luteal phase. Epithelial PR expression was lower under HRT compared with the early, but not the mid- or the late luteal phase. The number of PR-positive stromal cells under HRT was lower compared with the physiological cycle, and the difference was statistically significant in comparison with the early luteal phase (P < 0.05). The glandular area expressing human beta-lactoglobulin during the late progestogenic phase was statistically significantly higher compared with the early, but lower in comparison with the mid- or the late luteal phase (P < 0.05). The study demonstrates a sub-physiological progestogenic response superimposed on evidence of a hypo-oestrogenism, and a differential response in the epithelium and stroma.

Endometrium↗
PubMed2000

Effect of different cyclical sequential progestins on endometrial vascularity in postmenopausal women compared with the natural cycle: a morphometric analysis.

The effect of trimegestone-based and norethisterone-based hormone replacement therapy (HRT) regimens on the endometrial vascularity compared with that of the endometrium of the natural cycle were evaluated using immunohistochemical techniques. Endometrial vascular space area, diameter and number were defined in the functionalis layer of the endometrial samples from postmenopausal women who either completed a randomized, double blind, dose-ranging study of continuous oral micronized oestradiol 2 mg daily with trimegestone 0.05, 0.1, 0.25 and 0.5 mg/day from day 15-28 for six treatment cycles or were given cyclical sequential norethisterone (NET)-based HRT together with continuous 2 mg oral oestradiol valerate for three cycles. The control samples were LH-dated endometrial biopsies. NET-based HRT was associated with a higher number of smaller vascular spaces compared with the trimegestone-treated endometrium or that of the natural cycle. There was no dose-dependent effect in the four dose groups of trimegestone. In conclusion, norethisterone may exert a different effect on angiogenesis to that of trimegestone on endometrial vascular development.

Adult↗
PubMed2000

The effect of submucous fibroids on the dose-dependent modulation of uterine bleeding by trimegestone in postmenopausal women treated with hormone replacement therapy.

OBJECTIVE: To assess the value of identifying endometrial structural abnormalities at baseline hysteroscopy in predicting the pattern of bleeding in postmenopausal women treated with hormone replacement therapy. DESIGN: A randomised, double-blind, dose-ranging study. SETTING: A teaching hospital in the UK. POPULATION: One hundred and seventy-six healthy postmenopausal women. METHODS: Women were randomised to receive one of four doses of oral trimegestone (0.05, 0.1, 0.25 and 0.5 mg per day), from day 15-28, and a daily dose of 2 mg oral micronised oestradiol for six treatment cycles. Women completed diaries in which the bleeding episodes were recorded. Hysteroscopy under local anaesthesia and endometrial biopsy were performed at baseline and on day 24 of the last treatment cycle. RESULTS: Women with submucous fibroids had more prolonged (P = 0.026) and heavier (P = 0.002) progestogen-associated bleeding (odds ratio 4.54). The incidence of intermenstrual bleeding, but not its duration or severity, was higher in women with submucous fibroids (P = 0.017). There was a clear dose-dependent effect of trimegestone, with a consistently later onset of progestogen-associated bleeding occurring with increasing doses of trimegestone (P < 0.001), and such episodes became progressively lighter and of shorter duration over time (P < 0.001). CONCLUSION: Hysteroscopic evaluation of the endometrial cavity in women treated with hormone replacement therapy, predicts the occurrence of heavy and unscheduled bleeding.

Dose-Response Relationship, Drug↗