Endometrial vessel maturation in women exposed to levonorgestrel-releasing intrauterine system for a short or prolonged period of time

BACKGROUND: Levonorgestrel-releasing intrauterine system (LNG-IUS), although inserted to reduce heavy menstruation, causes irregular early transient bleeding. The objective of the study was to document quantitative changes in endometrial vessels of short- (< or =3 months) and long-term (> or =12 months) LNG users. The area, density and maturation of endometrial vessels were quantified in 19 endometrial biopsies of women with LNG-IUS and in 10 normally ovulating patients during mid-luteal phase. METHODS: Vessel maturation was evaluated by double immunostaining using anti-von Willebrand factor (endothelial cell marker) and anti-alpha Smooth Muscle Actin (vascular smooth muscle cells) antibodies. Vessel area, number and density were quantified with a novel computer-assisted image analysis system. RESULTS: Endometrium exposed to LNG-IUS for 1-3 months displayed a 11.5-fold increase in small naked vessel number. The partially mature vessel (alphaSMA partially positive) number increased six times. After long-term LNG-IUS treatment, the immature and partially mature vessel number remained four times higher than in the control group. Vessel area and density also increased dramatically in a time-dependent pattern with LNG-IUS use. CONCLUSIONS: Levonorgestrel affects blood vessel number, area, density and maturation in a time-dependent pattern that may explain the early transient increase in breakthrough bleeding with the LNG-IUS.     

The local progestational effect of the levonorgestrel-releasing intrauterine system: a sonographic and Doppler flow study

BACKGROUND: We aimed to evaluate the effect of the levonorgestrel-releasing intrauterine system (LNG-IUS) on the uterine vasculature and the endometrium. METHODS: The study was a prospective controlled study evaluating the local effects of LNG-IUS compared with the copper intrauterine device (IUD). Forty-seven women carrying LNG-IUS (group A) were compared with 35 women carrying copper IUD in a control group (group B). Clinical measures of menstrual bleeding, endometrial thickness and Doppler flow of the cervical branch of the uterine artery and spiral artery were evaluated and compared between the two groups. RESULTS: Doppler flow in the cervical branch of the uterine artery did not reveal any changes between the groups (resistance index = 0.6 +/- 0.01 in both groups). Endometrial width was significantly thinner in group A (4.1 +/- 0.2 mm) compared with group B (7.3 +/- 0.2 mm) (P < 0.0001). Subendometrial flow in the spiral artery was significantly reduced in 35 women of group A (75%) and in none of group B (P < 0.0001). CONCLUSIONS: The present study offers an explanation for the oligomenorrhoea in LNG-IUS users, i.e. a local progestational effect on the endometrium with no change in the blood flow in the uterine artery. This should be presented to the women in the pre-contraceptive counselling in order to lessen the discontinuation rate.     

The levonorgestrel-releasing intrauterine system (LNG-IUS) in HIV-infected women--effects on bleeding patterns, ovarian function and genital shedding of HIV

BACKGROUND: Safe and effective contraceptives are needed for human immunodeficiency virus (HIV)-infected women. The levonorgestrel-releasing intrauterine system (LNG-IUS) is a highly effective contraceptive with additional health benefits. The objective of this study was to evaluate the effects of the LNG-IUS among HIV-infected women. METHODS: Twelve systematically managed HIV-infected women were studied prospectively. Following a 2-month run-in period, the subjects had an LNG-IUS inserted and were followed up for 1 year. Patterns of bleeding, blood haemoglobin and CD4-lymphocyte content, plasma HIV RNA, serum levels of LNG, of estradiol (E(2)) and of ferritin and genital shedding of HIV RNA were monitored. RESULTS: Menstrual bleeding was reduced significantly during the use of the LNG-IUS; this was associated with slight increases in serum haemoglobin and ferritin levels. Serum E(2) concentrations remained in the follicular range in all subjects. Among subjects using antiretroviral medication, the proportion of cervicovaginal lavage specimens with detectable HIV RNA was 10% before and after the insertion of the LNG-IUS. CONCLUSIONS: The effects of the LNG-IUS on bleeding patterns, body iron stores and ovarian function were similar to those seen in healthy women. Genital shedding of HIV RNA was not affected by the LNG-IUS. These data encourage further studies on the effects of the LNG-IUS on reproductive health among HIV-infected women.     

Differential effects of oral conjugated equine estrogen and transdermal estrogen on atherosclerotic vascular disease risk markers and endothelial function in healthy postmenopausal women

BACKGROUND: Recent studies have revealed that HRT may increase the risk for atherosclerotic vascular disease (ASVD). METHODS: We investigated the effects of HRT via different administration routes on the markers for ASVD and endothelial function in healthy postmenopausal women. The oral HRT group (n=18) received conjugated equine estrogen 0.625 mg/day; the transdermal HRT group (n=18) received 17beta-estradiol (E2) gel 0.6 mg/day for 6 months. The control group (n=30) had no treatment for 6 months. RESULTS: The C-reactive protein (CRP) rose from 0.129+/-0.116 to 0.752+/-0.794 mg/dl (P<0.01) in the oral HRT group but remained unchanged in the transdermal HRT and control groups. The flow-mediated vasodilation (FMD) in the brachial artery was increased significantly by HRT from 6.0% before oral HRT to 14.7% after oral HRT (P<0.001) and from 5.9% before transdermal HRT to 13.9% after transdermal HRT (P=0.001). CONCLUSIONS: These data suggest that oral estrogen induces ASVD risk by increasing acute inflammation; however, transdermal estrogen avoids this untoward effect. Additionally, transdermal estrogen exerts a positive effect on endothelial function similar to that of oral estrogen. Therefore, the transdermal route might be favourable in terms of ASVD risks.     

Expression of vascular endothelial growth factors and their receptors in human endometrium from women experiencing abnormal bleeding patterns after prolonged use of a levonorgestrel-releasing intrauterine system

BACKGROUND: Menstrual bleeding disturbances are a common initial complaint among users of the levonorgestrel-releasing intrauterine system (LNG-IUS). In this study, women who experienced bleeding disturbances recurring after a previous period of problem-free use and who therefore wanted removal of their LNG-IUD were investigated. Vascular endothelial growth factors (VEGFs) and their receptors are thought to be involved in normal endometrial angiogenesis. The aim of the study was to elucidate the possible association of these VEGF and receptors with bleeding disturbances among users of LNG-IUS. METHODS: Endometrial biopsies were obtained from users of the LNG-IUS who complained of bleeding disturbances (n = 17) and from women without such problems (n = 14). The endometrial expression of these VEGFs and their receptors was analysed using immunohistochemistry. RESULTS: Endometrial endothelial cells from LNG-IUS users with menstrual bleeding disturbances exhibited significantly higher immunoreactivity for VEGFR-1 and VEGFR-3 than those from women without bleeding disturbances. Stromal cells showed significantly lower immunoreactivity for VEGF-A in samples from LNG-IUS users with bleeding disturbances than in those without. CONCLUSION: Changes in the expression of these angiogenic growth factors and their receptors in LNG-IUS-exposed endometrium might be involved in the formation of fragile and dysfunctional blood vessels that subsequently give rise to bleeding disturbances.     

Hormone replacement therapy: pathobiological aspects of hormone-sensitive cancers in women relevant to epidemiological studies on HRT: a mini-review

Hormone replacement therapy (HRT) has gained widespread and in some areas indiscriminate use. In reference to recent epidemiological studies which showed unexpected and controversial associations of HRT use with malignant tumours, here we review the current understanding of the dynamics of tumour growth. The pathomorphological characteristics and sex hormone sensitivity of cancers of the breast, endometrium, ovary and colon are discussed. The development of cancer from the first malignant tumour cell to clinical diagnosis takes many years. Hormones can influence tumour growth, but it is questionable whether hormones induce malignant tumours de novo. It is much more likely that hormones 'merely' promote the growth of already existing tumour cells. The long developmental process of tumours is in apparent contradiction to results of some epidemiological studies that describe an increased cancer risk, implying primary initiation, in HRT users within observation periods of 1-6 years. The mechanisms of initiation versus promotion of hormone-sensitive cancers, particularly breast cancer, are only partly understood. The conventional methods of epidemiological studies cannot detect potential risk factors without bias if they do not include a pathomorphological component on growth characteristics. The results of previous studies should be interpreted with great caution with regard to tumour biology.     

Differential elevation of matrix metalloproteinase expression in women exposed to levonorgestrel-releasing intrauterine system for a short or prolonged period of time

BACKGROUND: The levonorgestrel-releasing intrauterine system (LNG-IUS) isan effective contraceptive and has many non-contraceptive healthbenefits. However, it is commonly associated with irregularendometrial bleeding. Metalloproteinases contribute to extracellularmatrix (ECM) remodelling and regulate bleeding during the menstrualcycle. Enhanced metalloproteinase expression participates inthe pathogenesis of breakthrough bleeding. Thus the objectiveof this study was to compare matrix metalloproteinase (MMP)expression in endometrium during luteal phase and in short-term(1 month) and long-term (6 months) LNG-IUS users. METHODS: MMP expression was analysed by semi-quantitative RT-PCR andimmunohistochemistry. Gelatinase activity was determined bygelatin zymography. RESULTS: MMP-1, -2, -3, -7, -9 and -12 mRNAs levels were increased, whereasthat of MMP-26 was decreased in the endometrium of LNG-IUS users.MMP-1, -2, -3, -7 and -9 were localized by immunohistochemistryin all biopsies in the short-term group but in only 0–27%in the control group. The incidence of positive immunostainingfor MMP-2 and -3 decreased significantly in the long-term comparedwith short-term LNG-IUS users. MMP-26 was localized in all biopsiesfrom the control group but in only 14 and 25% from the short-and long-term LNG-IUS groups, respectively. In both LNG groups,the numbers of macrophages (the major source of MMP-12) wasincreased. CONCLUSIONS: MMP-1, active MMP-2, MMP-3, MMP-7, MMP-9 and MMP-12 are moreprevalent in the short-term LNG-IUS group, suggesting theirimportant contribution to ECM breakdown and transient bleeding.The decrease in the percentage of women expressing MMP-2 and-3 might contribute to the decreased occurrence of unwantedspotting and bleeding in long-term LNG-IUS users.     

Endometrial suppression with a new 'frameless' levonorgestrel releasing intrauterine system in perimenopausal and postmenopausal women: a pilot study

OBJECTIVE: A novel intrauterine drug delivery system, FibroPlant-levonorgestrel (LNG), derived from the frameless GyneFix intrauterine device (IUD) is described and the preliminary results in 30 symptomatic climacteric and postmenopausal women are discussed. The treatment with the FibroPlant-LNG intrauterine system (IUS) was instituted to suppress the endometrium during estrogen substitution therapy (EST) to prevent endometrial proliferation and bleeding. The purpose of the study was to evaluate the clinical and ultrasonographic effect of this new intrauterine progestin delivery system. METHODS: Two dosage forms were tested: the first 11 women received a 3-cm long coaxial fibrous delivery system, delivering approximately 10 microg per day of LNG; the remaining 19 women in the study received a 4-cm long delivery system, delivering approximately 14 microg per day. The calculated duration of release of the two systems is approximately 5 years. Twenty-two women were perimenopausal at the start of the treatment. Women in this study were observed for a duration of at least 1 year. Most postmenopausal women received percutaneous 17beta-estradiol (Oestrogel), 1.5 mg daily on a continuous basis. RESULTS: All postmenopausal women in the two groups reported amenorrhea during the entire study period (up to two and a half years follow-up). Endometrial atrophy in these women was confirmed by vaginal ultrasound examination. Seventeen of the 22 perimenopausal women reported amenorrhea at the first or second follow-up visit at 1 and 3 months following insertion of the IUS, respectively. The remaining had infrequent scanty bloody discharge needing a panty liner, at the most, for protection. There were no complications in this study (e.g. infection, expulsion or perforation). The FibroPlant-LNG IUS was very well tolerated by all the women and no systemic hormonal side effects were reported. There were no removals for medical reasons. CONCLUSION: The results of this pilot study suggest that the frameless FibroPlant-LNG IUS is safe, well tolerated and effective in suppressing the endometrium during EST. No differences could be clinically distinguished between the two dosages. Compliance was optimal. The fact that the IUS also acts as a potent contraceptive is of added importance.     

Correlation between endometrial histology, microvascular density and calibre, matrix metalloproteinase-3 and bleeding pattern in women using a levonorgestrel-releasing intrauterine system

BACKGROUND: The main reason for discontinuation of the levonorgestrel-releasing intrauterine system (LNG-IUS) is unpredictable bleeding pattern. METHODS: The objective of the study was to evaluate the endometrial histology, microvascular density and calibre, and the quantification of matrix metalloproteinase (MMP-3) in long-term users of LNG-IUS, with and without bleeding. Endometrial biopsies were obtained from 58 healthy women, 29 who maintained some degree of endometrial bleeding and 29 who were amenorrhoeic. RESULTS: In the histological analysis, the majority of samples displayed a progestin-modified appearance. The major glandular diameter and the perimeter were significantly greater in the group of women with amenorrhoea. A significantly higher number of leukocytes was found in the group with bleeding (P = 0.014). No significant correlation was observed between the microvascular density or calibre and the bleeding pattern. MMP-3 showed a significantly higher number of reactive cells (P = 0.005) in the group who maintained some degree of bleeding. CONCLUSIONS: Women using LNG-IUS who maintained endometrial bleeding during its use presented a higher number of leukocytes and MMP-3 in the endometrium when compared to women using LNG-IUS who became amenorrhoeic. However, the results did not provide evidence for microvascular pattern changes.     

Mechanism of action of the intrauterine contraceptive device: evidence for a specific biochemical deficiency in the endometrium

The precise mechanism of action of the intrauterine contraceptivedevice (IUCD) is uncertain. In this study we compared the circulatingconcentrations of a specific endometrial protein, placentalprotein 14 (PP14), in 62 women with an IUCD and 16 controls.The concentrations of PP14 were substantially lower in IUCDusers. There was no difference in the concentrations of anotherand less specific endometrial protein, insulin-like growth factorbinding protein-1 (IGFBP-1). There was no difference in PP14concentrations between those women with and without intermenstrualbleeding. We conclude that the reduced concentrations of PP14in IUCD users reflect defective endometrial function in thesewomen, probably related to the contraceptive effect We proposethat the measurement of PP14 might be a means of comparing theefficiency of different devices.     

Bleeding patterns in peri and postmenopausal women taking a continuous combined regimen of estradiol with norethisterone acetate or a conventional sequential regimen of conjugated equine estrogens with medrogestone

Objectives: The aim of this study was to compare the incidence of women presenting irregular bleeding episodes following 9 months of treatment with a low dose continuous combined hormone replacement therapy consisting of estradiol (E₂) and norethisterone acetate (NETA) versus a sequential hormone replacement therapy consisting of conjugated equine estrogens (CEE) and medrogestone (MG). Secondary aims were to establish the relationship between menopausal age and the occurrence of irregular bleeding for both therapies and to assess the efficacy of both therapies in alleviating menopausal symptoms. Methods: This was a stratified and randomised, open label study conducted with late peri and postmenopausal women at 35 sites in Austria and Germany. A total of 446 women were randomly allocated into two cohorts based on time since last bleeding and then stratified to either a low dose continuous combined therapy consisting of 1 mg E₂ and 0.5 mg NETA for 28 days or a sequential therapy consisting of 0.625 mg CEE for 28 days and 5 mg MG for the final 14 days. Bleeding and menopausal complaints were continuously assessed. Treatments were administered for 9 lunar months. Results: The incidence rate of women presenting irregular bleeding episodes including spotting during cycle 9 was 12.2% with 1mgE₂/0.5mgNETA and 25.8% with 0.625mgCEE/5mgMG (P=0.0014). In the group of postmenopausal women (time since last bleeding 12 months) the incidence of irregular bleeding during cycle 9 was 11.0% for 1mgE₂/0.5mgNETA and 25.0% for 0.625mgCEE/5mgMG). In the group of late perimenopausal women (time since last bleeding 6–11 months) the incidence of irregular bleeding was similar for both treatments at cycle 3, but markedly less in patients with 1mgE₂/0.5mgNETA at cycle 6 and 9, being significantly different compared to patients with 0.625mgCEE/5mgMG at cycle 6 (P<0.05). The cumulative rate of amenorrhea (no bleeding or spotting) achieved with 1mgE₂/0.5mgNETA was 89% for the postmenopausal women and 83.7% for the late perimenopausal women. Both treatments relieved menopausal complaints equally effective. Conclusions: Regarding the occurrence of irregular bleeding, the low dose continuous combined therapy was superior to the sequential therapy (0.625mgCEE/5mgMG). The low dose continuous combined E₂/NETA regimen is also suitable for late perimenopausal women since more than 80% of the women had no bleeding or spotting after 9 months of treatment.     

Endometrial CD56+ natural killer cells in women with recurrent miscarriage: a histomorphometric study.

Endometrial natural killer (NK) cells were compared in luteal-phase endometrial samples from women with recurrent miscarriage and from normal subjects. Cryostat sections were labelled using a monoclonal antibody to CD56 using an avidin-biotin complex method and a morphometric study performed. Increased mean numbers of CD56+ cells were documented in the endometrium of women with recurrent early miscarriage only. These findings suggest a possible role for NK cells in the pathogenesis of recurrent early pregnancy loss.     

Combined treatment by pentoxifylline and tocopherol for recipient women with a thin endometrium enrolled in an oocyte donation programme

BACKGROUND: To evaluate the effect of an antifibrotic treatment by a combination of pentoxifylline (PTX) and tocopherol (vitamin E) in patients with a thin endometrium who were enrolled in an oocyte donation programme. METHODS: Eighteen oocyte recipients who failed to develop a pre-ovulatory endometrial thickness of at least 6 mm after receiving vaginal micronized estradiol were enrolled in the study. The patients received a combination of PTX (800 mg/day) and vitamin E (1000 IU/day) for 6 months. The main outcome measurements were the change in endometrial thickness and the pregnancy and delivery rates after treatment. RESULTS: Endometrial thickness increased significantly (P <0.001), with a mean of (+/-SD) 4.9 +/-0.6 mm before and 6.2 +/- 1.4 mm after treatment, with 72% (13/18) of patients being good responders. Five patients either did not respond to the treatment or responded only slightly. Three patients, of which two had received previous radiotherapy, became spontaneously pregnant, and two became pregnant after embryo transfer. Three patients did not have embryo transfer. A total of four babies were delivered. The pregnancy rate was thus 33% and the delivery rate 27%. CONCLUSION: Treatment by combination of PTX and vitamin E appears to improve the pregnancy rate in patients with a thin endometrium by increasing the endometrial thickness and improving ovarian function. This was especially noticeable in patients who had previously received total body irradiation.     

Comparison of the effects of a new conjugated oral estrogen, estradiol-3beta-glucoside, with oral micronized 17beta-estradiol in postmenopausal women

The objective of this article is to evaluate the pharmacokinetics of serum estrone and estradiol levels in women who were taking either 17beta-estradiol-3beta-glucoside (E(2)-3beta-glucoside) or 17beta-estradiol (E(2)) daily and to examine the effects of E(2)-3beta-glucoside and E(2) on postmenopausal symptoms, gonadotropins, hepatic metabolism, and coagulation factors. Healthy postmenopausal women on estrogen who had undergone a hysterectomy were recruited. Subjects were randomly assigned to receive equivalent doses of either E(2)-3beta-glucoside or micronized E(2) for 28 days. Pharmacokinetic studies of estrone and estradiol were performed on days 1, 2, 28, and 29. Gonadotropin levels and Kupperman Index (KI) scores were determined at baseline and on treatment day 28. Mean serum estradiol and estrone concentrations in those taking E(2)-3beta-glucoside were comparable with those taking E(2). Mean baseline follicle stimulating hormone (FSH) levels were 84 +/- 27 mIU/mL and 71 +/- 24 mIU/mL in the E(2)-3beta-glucoside and E(2) groups, respectively, with significant decreases (P < 0.01) of 54 +/- 21 mIU/mL and 38 +/-18 mIU/mL, respectively, by treatment day 28. Baseline KI scores in the E(2)-3beta-glucoside group were 10 +/- 6 compared with 5 +/- 4 on treatment day 28, which is equivalent to a 50% reduction in menopausal symptoms (P = 0.003). The change in KI scores in the E(2) group was not statistically significant. Total serum estradiol and estrone levels in women taking E(2)-3beta-glucoside are comparable with those in women taking E(2). E(2)-3beta-glucoside reduces serum gonadotropin levels to the premenopausal range and is effective at reducing postmenopausal symptoms. E(2)-3beta-glucoside is a novel synthetic estrogen that is well tolerated and has promise as a hormone replacement therapy.     

Markers of endometrial function in women with unexplained recurrent pregnancy loss: a comparison between morphologically normal and retarded endometrium

BACKGROUND: Endometrial defect, usually described as luteal phase defect (LPD), is associated with recurrent miscarriage. Recurrent miscarriage has also been associated with the abnormal expression of various molecules by endometrial cells. The aim of this study was to determine if any of these molecules or cells could be used to distinguish LPD from in-phase endometrium. METHODS: Immunocytochemistry was used to compare endometrial expression of CD45+, CD56+, CD3+ and CD4+ cells, leukaemia inhibitory factor, interleukin-6 and estrogen and progesterone receptors in precisely timed endometrial biopsies obtained between days LH+6 and LH+11 from recurrent miscarriage women with in-phase and retarded endometrium. RESULTS: In all samples there was a positive correlation between the number of CD45+ cells and LH day and a negative correlation between progesterone receptor and LIF expression and LH day. A significantly lower number (P<0.05) of CD56+ cells in peri-implantation endometrium and a decreased mid-cycle estrogen level (P<0.05) was seen in women with LPD compared to in-phase endometrium when single analysis was carried out. However, these differences were not significant after application of the Bonferroni correction for multiple analysis. CONCLUSIONS: The results are in line with previous associations observed between estrogen levels and LPD and suggest that the number of CD56+ cells is different in LPD and in-phase endometrium, although this could be due to delayed endometrial development in women with LPD. Interpretation must be cautious because these differences could have arisen by chance.     

Endometrial breakdown in women using Norplant is associated with migratory cells expressing matrix metalloproteinase-9 (gelatinase B)

Norplant, subdermally implanted slow-release levonorgestrel, is an effective and widely used contraceptive agent but has a high rate of discontinuation due to unacceptable abnormal uterine bleeding. Matrix metalloproteinases (MMPs) are expressed in normal cycling endometrium and are postulated to be responsible for the tissue breakdown at menstruation. We have compared the immunolocalization of MMP-9 and migratory cells in endometrium from Indonesian women using Norplant with normal controls. Positive MMP-9 immunostaining was observed intracellularly within stromal and intravascular leukocytes and extracellularly in areas of tissue lysis adjacent to these migratory cells. The MMP-9 positive cells were identified as neutrophils, eosinophils, CD3+ T-cells and macrophages. Quantitative assessment revealed that the number of MMP-9 positive cells, neutrophils and eosinophils were significantly increased in those endometrial biopsies from Norplant users displaying a shedding morphology and in normal controls at menstruation. There was no correlation between the number of MMP-9 positive cells and the number of bleeding days reported. Endometrial immunostaining for tissue inhibitor of metalloproteinases was similar in Norplant users and normal controls. These results suggest that MMP-9, an enzyme capable of degrading basement membrane components, may be involved in endometrial breakdown in women using Norplant.     

Pregnancy: Serum placental protein 14 concentrations are similar in the first trimester pregnancies of women after pituitary down-regulation with a gonadotrophin-releasing hormone agonist and normal cycles with frozen embryo transfers

Previous studies suggest that, in pregnancies after in-vitrofertilization (IVF) and embryo transfer following pituitarydown-regulation with a gonadotrophin-releasing hormone analogue(buserelin) and ovulation induction with human gonadotrophins,the serum placental protein 14 (PP14) concentration is lowerthan in normally conceived pregnancies. We studied serum PP14concentrations in two groups of women: (i) in 17 infertile womenwhose pregnancy followed IVF and embryo transfer using buserelin(long protocol) and human menopausal gonadotrophin for ovulationinduction; (ii) in 15 women whose pregnancy followed transferof frozen-thawed embryos. Similar PP14 concentrations were foundin both groups on days 9–10, 14–15 and 70–77after human chorionic gonadotrophin administration (buserelin,IVF/embryo transfer) or spontaneous luteinizing hormone surge(frozen-thawed embryo transfer). Our results show that PP14secretion is not compromised by pituitary down-regulation withbuserelin in infertile women with functional ovaries.     

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.     

Raloxifene lowers serum lipoprotein(A) in healthy postmenopausal women: a randomized, double-blind, placebo-controlled comparison with conjugated equine estrogens.

OBJECTIVE: Long-term postmenopausal estrogen replacement therapy lowers the risk of osteoporotic fractures and coronary artery disease but increases the risk of endometrial cancer and probably breast cancer. Raloxifene, a nonsteroidal estrogen receptor ligand, seems to have a tissue-specific antiestrogenic action on endometrium and breast and the desired estrogenic action on bone and lipid metabolism. The purpose of this study was to investigate the effects of 24-month treatment with orally administered raloxifene in two doses (60 mg and 150 mg daily) and conjugated equine estrogens in a standard oral dose (0.625 mg daily) on serum lipoprotein(a) [Lp(a)], an independent risk factor for coronary artery disease, in healthy postmenopausal women who had undergone hysterectomy. DESIGN: A randomized, double-blind, placebo-controlled study was performed with 56 women. RESULTS: In the placebo group serum Lp(a) levels did not change throughout the study. After 6 months, serum Lp(a) was significantly reduced versus baseline in the raloxifene 150 (-17%; p = 0.003) and conjugated equine estrogens (-26%; p = 0.003) groups, but this reduction was significantly different from placebo only in the conjugated equine estrogens group. At 12 and 24 months, serum Lp(a) levels were significantly lowered versus baseline in all active treatment groups. However, these reductions were significantly different from placebo only in the raloxifene 150 and conjugated equine estrogens groups. After 24 months, serum Lp(a) was reduced versus baseline with 30% (p = 0.001) in the raloxifene 150 group and 35% (p = 0.001) in the conjugated equine estrogens group. CONCLUSIONS: Long term raloxifene treatment significantly lowers serum Lp(a) levels in postmenopausal women and thus might reduce the risk of coronary artery disease.