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Biomedical subjects

M Wahab

Publications and source records attributed to M Wahab.

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↗
PubMed2006

Monte carlo simulations of self-assembled surfactant aggregates.

Monte Carlo simulations provide some insight into the self-assembly of amphiphiles in aqueous environment. A rather simple solvent-free model, with only two adjustable parameters in the effective pair potential, allows one to describe the formation of micelles, stable curved membranes, and metastable vesicles. Characteristic features of the self-assembled aggregates, such as the distribution of the micelle size and the value of the curvature elastic constant for membranes, can be obtained from simulated data. The capability of the simple approach was demonstrated for a surfactant model with three spherical segments. The extension of the simulation to molecules with more segments and branched amphiphiles is straightforward.

Journal Article↗
PubMed2005

Monte Carlo study of surfactant adsorption on heterogeneous solid surfaces.

The equilibrium between free surfactant molecules in aqueous solution and adsorbed layers on structured solid surfaces is investigated by lattice Monte Carlo simulation. The solid surfaces are composed of hydrophilic and hydrophobic surface regions. The structures of the surfactant adsorbate above isolated surface domains and domains arranged in a checkerboard-like pattern are characterized. At the domain boundary, the adsorption layers display a different behavior for hydrophilic and hydrophobic surface domains. For the checkerboard-like surfaces, additional adsorption takes place at the boundaries between surface domains.

Journal Article↗
PubMed2004

Adhesion force of a wedge.

The macroscopic theory of capillarity is usually applied to evaluate the adhesion forces produced by fluid bridges between solid particles. A refined mesoscopic description incorporates the disjoining pressure, which results from the long range forces between the fluid and the solid substrates. In the case of simple nonpolar fluids the influence of the disjoining pressure on adhesion is expected to be negligibly small. Water bridges, however, sometimes have very large disjoining pressures on various substrates. Then mesoscopic theory leads to pull-off forces which differ from the predictions of the macroscopic approach.

Journal Article↗
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↗
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

Estrogen and colon cancer: current issues.

Carcinoma of the colon is common and its incidence varies according to the geographical location and dietary habits. The aims of this paper are, first, to review the current epidemiological data on the incidence and mortality of colon cancer in postmenopausal women using hormone replacement therapy (HRT); second, to review the published data on the prevalence of estrogen receptors in healthy and malignant colonic tissue; and third, to examine the available evidence of gene silencing as applicable to this and other neoplastic conditions. Estrogen use confers overall protection, with a reduction in the incidence of colon adenoma and carcinoma of about 30%. Estrogen use reduces the colon cancer-related mortality. The risk of colon cancer is decreased among current and recent users of postmenopausal HRT but the molecular mechanisms involved remain unclear. Estrogen acts either on a single major transformation step in the oncogenetic process, or is involved in multiple events that avert the course of this transformation. Aberrant methylation of the CpG islands in the promoter regions of the estrogen receptor gene, as well as of other genes, is equivalent to the silencing of that gene, with the consequence of inactivation, or reduced expression, of a number of genes downstream, including tumor suppressor genes. This epigenetic mechanism, when reversed, suppresses the growth of cancer cells in vitro and in vivo. The ubiquitous distribution of the estrogen receptor genes and their isoforms, in a tissue-specific manner, opens new avenues for the understanding of cellular behavior in health and disease.

Breast Neoplasms↗
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

Acceptability and patterns of endometrial bleeding in estradiol-based HRT regimens: a comparative study of cyclical sequential combinations of trimegestone or norethisterone acetate.

OBJECTIVE: This randomized, double-blind, multicenter study was planned to compare the efficacy and tolerance of a novel oral regimen containing estradiol (2.0 mg) sequentially combined with trimegestone, at a daily dose of either 0.25 mg or 0.5 mg, with a standard hormone replacement therapy containing estradiol and norethisterone acetate (E2 + NETA) in the treatment of climacteric symptoms. METHODS: The study was conducted over 13 cycles, each of 28 days, and involved 487 subjects, of whom 349 completed the study. RESULTS: All three treatments were equally effective in alleviating hot flushes and showed a progressive and significant reduction in the value of the Kupperman index. The treatments diminished equally effectively urogenital signs and symptoms. All treatments were well tolerated and the incidences of adverse events associated with each treatment were similar across the treatment groups. The duration of expected withdrawal bleeding was shorter in the estradiol + trimegestone 0.5 mg group than in the estradiol + trimegestone 0.25 mg or E2 + NETA group. CONCLUSION: All treatments were effective and well tolerated, providing significant relief from climacteric symptoms. Treatment with estradiol + trimegestone 0.5 mg provided the most favorable bleeding pattern.

Argentina↗
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↗
PubMed1999

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↗
PubMed1999

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↗
PubMed1999

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↗
PubMed1999

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↗