Endometrial safety after 5 years of continuous combined transdermal estrogen and intrauterine levonorgestrel delivery for postmenopausal hormone substitution

OBJECTIVE: To investigate endometrial histology and thickness of the endometrium after long-term use of continuous transdermal estrogen substitution combined with intrauterine release of levonorgestrel (LNG) in postmenopausal women. DESIGN: A 5-year non-comparative prospective clinical trial. SUBJECTS: Out of 182 symptomatic postmenopausal women using estrogen substitution therapy (EST) combined with a novel T-shaped LNG-releasing intrauterine system (Femilis Slim LNG-IUS), to prevent endometrial proliferation and bleeding, only those women (n=102) who used two consecutive LNG-IUSs, were isolated with the aim to study the long-term effects on the endometrium. The mean age of the women was 57 years (range 47-71). The majority of women received percutaneous 17beta estradiol, 1.5mg daily, or an equivalent dose by patch or orally, on a continuous basis. MAIN OUTCOME MEASURES: Endometrial histology and ultrasonographic evidence of endometrial suppression, after a period of approximately 5 years of use. The mean duration of use of the regimen was 70 months (range 25-98). RESULTS: The dominant endometrial histologic picture was that of inactive endometrium characterized by glandular atrophy and stroma decidualization (Kurman classification 5b). No cases of endometrial hyperplasia were found. On transvaginal ultrasound, this corresponds with a thin endometrium (< or = 5 mm). CONCLUSION: The results of this 5-year study in 102 postmenopausal women using EST demonstrates that the LNG-IUS effectively opposes the estrogenic effect on the endometrium resulting in strong suppression during the entire period of EST. Due to its high efficacy and absence of systemic effects on organ tissues (e.g., breasts), target delivery in the uterine cavity could be a preferred route to administer a progestagen in women using EST.     

Levonorgestrel intrauterine system (LNG-IUS) with conjugated oral equine estrogen: a successful regimen for HRT in perimenopausal women

BACKGROUND: This study was designed to assess the long-term efficacy (5 years) of the levonorgestrel-releasing intrauterine system (LNG-IUS) in protecting the endometrium from hyperplasia during estrogen replacement therapy in perimenopausal women. METHODS: Prospective, open, outpatient clinical trial in London and Oxford. Eighty-two women received oral conjugated equine estrogen 1.25 mg daily and LNG-IUS releasing 20 mug levonorgestrel per 24 h. Endometrial biopsy and histological assessment were performed annually. Endometrial thickness was measured by vaginal ultrasonography. RESULTS: Non-proliferative endometrium was present at the end of cycles 12, 24, 36, 48 and 60 in 98.6, 98.6, 95.5, 96.8 and 95.2% of the participants respectively. No endometrial hyperplasias were confirmed throughout a period of 60 cycles. The proportion of amenorrhoeic women increased from 54.4% at 12 cycles to 92.7% at the end of the study. The continuation rate per 100 women at 60 cycles was 79.84 (95% CI 71.0-88.6). CONCLUSIONS: The LNG-IUS with estrogen supplementation in perimenopausal women suppresses endometrial proliferation resulting in amenorrhoea and relieves vasomotor symptoms. The treatment regimen is well tolerated and provides an alternative strategy for perimenopausal women with the likelihood of increasing compliance.     

Differential diagnosis of endometrial hyperplasia and carcinoma by computerized image cytometry of cell proliferation, apoptosis and Bcl-2 expression.

BACKGROUND: The differential diagnosis between atypical endometrial hyperplasia and endometrial carcinoma is often difficult and based on controversial criteria. Cell kinetic parameters may be helpful. DESIGN: Cell proliferation, apoptosis and Bcl-2 expression were evaluated in benign endometrium, non atypical and atypical endometrial hyperplasia and endometrial carcinoma. The results were compared by one way analysis of variance and Bonferroni T tests. RESULTS: Cell proliferation was significantly higher (p < 0.01) in endometrial adenocarcinoma (25.6 percent) than in atypical hyperplasia (17.1 percent) and non-atypical hyperplasia (7.5 percent) of the endometrium. Apoptosis was observed in 12.3 percent of endometrial adenocarcinomas and less frequently in atypical hyperplasia (7.4 percent) and non-atypical hyperplasia of the endometrium (5.8 percent). Bcl-2 expression was significantly lower (p < 0.002) in endometrial adenocarcinoma (1.7 percent) than in atypical hyperplasia (4.2 percent) and non-atypical hyperplasia (5.3 percent) of the endometrium. In benign endometrium, cell proliferation and Bcl-2 expression were significantly higher during the proliferative phase while the rate of apoptosis was significantly higher during the secretory phase. CONCLUSIONS: Our data suggests that cell proliferation, apoptosis and Bcl-2 expression could be helpful when distinguishing endometrial carcinoma from non-atypical or atypical endometrial hyperplasia.     

Morphological and functional features of endometrial decidualization following long-term intrauterine levonorgestrel delivery

Irregular bleeding remains a common reason for the discontinuation of progestin-only contraception. The levonorgestrel releasing intrauterine system (LNG-IUS) has profound morphological effects upon the endometrium. Specific features are gland atrophy and extensive decidual transformation of the stroma. Morphological changes in the endometrium may be associated with perturbation of mechanisms regulating normal endometrial function. This study describes endometrial stromal and glandular features prior to and up to 12 months following insertion of the LNG-IUS. Comparison is made with first trimester decidua. In order to elucidate further mechanisms governing endometrial function with local intrauterine delivery of LNG, we here report histological features consistent with decidualization; a significant increase in granulocyte-macrophage colony stimulating factor (GM-CSF) immunoreactivity in decidualized stromal cells; glandular and stromal prolactin receptor expression and an infiltrate of CD56 + large granular lymphocytes and CD68 + macrophages. We are unaware of previous reports which have documented longitudinally both morphological and functional observations in endometrium exposed to local intrauterine levonorgestrel delivery. These studies demonstrate that long-term administration of intrauterine levonorgestrel results in features of altered morphology and function. No correlation was apparent between the end points in the study and the bleeding patterns described by the subjects. Further evaluation of these features in the context of menstrual bleeding experience may contribute to a better understanding of this troublesome side-effect which often leads to dissatisfaction and discontinuation of the intrauterine system.      

Continuous combined parenteral estrogen substitution and intrauterine progestogen delivery: the ideal HST combination?

OBJECTIVE: To evaluate ease of insertion, acceptability and endometrial safety of a novel, miniature intrauterine, T-shaped, levonorgestrel (LNG)-releasing intrauterine system (IUS), Femilis Slim LNG-IUS (Contrel Research, Belgium), combined with parenteral estrogen substitution therapy (EST) in postmenopausal women. DESIGN: A prospective, non-comparative, study in postmenopausal women. A 3.0 cm long and 2.0 mm wide coaxial fibrous delivery system, delivering approximately 20 microg/day of levonorgestrel (LNG) was used. The drug compartment is provided with crossarms fixed to the upper part of the drug delivery rod. The calculated duration of release of the system is at least 5 years. The majority of women received percutaneous 17beta estradiol (Oestrogel, Besins Int., Belgium), 1.5 mg daily on a continuous basis, which provides sufficient blood levels of estrogen in most women to suppress climacteric symptoms and protection against bone loss. Primary outcome measures: ease of insertion, retention and side effects of the T-LNG Slim IUS. Secondary outcome measures: endometrial safety assessed by transvaginal ultrasound examination and by endometrial biopsy in a subset of women. RESULTS: One hundred and seventy insertions were performed in postmenopausal women with median age of age 56.6 (range 43.5-80.3). Insertion was easy in 161 (94.2%) and difficult in 9 (5.3%) women. Pain at insertion was rated as none in 57 women (33.5%), mild in 105 (61.7%), moderate in 7 (4.1%) and severe in 1 (0.5%) woman. The system was well retained in the uterus as no expulsions occurred. At the time of study analysis, the total number of women-months was 1797.5. Ninety-five women had the T-LNG-IUS in place for periods in excess of 1 year. The study was well followed-up with lost-to-follow-up rate (defined as no follow-up during 12 months) of zero at the time of study analysis. The number of women continuing the method was 160 (94.1%) including four women which were released from follow-up for various non-medical related reasons. The histological examinations conducted in 105 women showed predominantly inactive endometrium characterized by a pseudo-decidual reaction of the endometrial stroma with endometrial atrophy. The mean thickness (double-layer) of the endometrium was 3.3 mm (range 2-5 mm) which correlated well with the histology results. CONCLUSIONS: The results suggest that the small T-LNG-IUS is easy to insert in most postmenopausal women without anaesthesia and dilatation of the cervix. It is well tolerated, well accepted and effective in suppressing the endometrium during EST. The lack of expulsions of the device in this study is attributed to the optimal design characteristics of the IUS, the absence of uterine bleeding and absent or reduced contractility of the uterus. The study confirms earlier studies conducted with other LNG-releasing systems used for endometrial suppression during EST. The ease of insertion of the small LNG-IUS could be an important incentive to expand the use of the continuous combined regimen with local delivery of the progestogen. It could be a method of choice for endometrial suppression in women using EST with fundamental advantages to systemically applied progestogens which have been the subject of considerable debate as reported in the recent literature.     

Local levonorgestrel regulation of androgen receptor and 17beta-hydroxysteroid dehydrogenase type 2 expression in human endometrium

BACKGROUND: The levonorgestrel-releasing intrauterine system (LNG-IUS) is a highly effective contraceptive. However, unscheduled breakthrough bleeding (BTB), leads to discontinuation in a proportion of users. The LNG-IUS down-regulates endometrial progesterone and estrogen receptors and this may play a role in the mechanism responsible for BTB. LNG is an androgenic progestogen and so we examined the regulation of the androgen receptor (AR) in endometrium exposed to intrauterine LNG. Furthermore, as the enzyme 17beta-hydroxysteroid dehydrogenase type 2 (17betaHSD2) regulates intracellular levels of estrogens, progestins and androgens, we evaluated the changes in expression of 17betaHSD2 in the same tissue endometrial samples. METHODS: Immunohistochemistry and real time quantitative RT-PCR were used to compare protein and mRNA expression of AR and 17betaHSD2 in endometrial biopsies from women with normal menstrual cycles and those using a LNG-IUS. RESULTS: Immunohistochemistry showed that AR and 17betaHSD2, which were immunolocalized to the stroma and glands of endometrium respectively, were both suppressed by LNG-IUS treatment, though moderate staining of 17betaHSD2 was evident 1 month after insertion of the LNG-IUS. AR mRNA expression was down-regulated in LNG-exposed endometrium when compared with the proliferative phase of the menstrual cycle. 17betaHSD2 mRNA was significantly increased 3 months (but not 6-12 months) after LNG-IUS insertion. CONCLUSIONS: Endometrial intracellular estradiol levels would have been suppressed by 17betaHSD2 during the first few, but not the later, months of LNG-IUS action, and the lowered endometrial estradiol level may contribute to the frequent BTB evident in the early months of LNG-IUS use. The subsequent decline in 17betaHSD2 would lead to elevated local intracellular estradiol in the later months, when the BTB tends to subside. The suppression of AR by the LNG-IUS may also play a role in BTB, as elevated AR has been associated with amenorrhoea.     

Endometrial safety with a low-dose intrauterine levonorgestrel-releasing system after 3 years of estrogen substitution therapy

OBJECTIVE: To evaluate the pharmacodynamic effects of a novel intrauterine drug delivery system, FibroPlant-levonorgestrel (LNG), on the endometrium in 24 postmenopausal women using estrogen substitution therapy (EST) to suppress climacteric symptoms. DESIGN: A 3-year non-comparative prospective clinical trial. SUBJECTS: The treatment with the FibroPlant-LNG intrauterine system (IUS), releasing 14 microg of LNG per day, was part of a regimen for estrogen substitution therapy in symptomatic postmenopausal women to prevent endometrial proliferation and bleeding. The majority of women received percutaneous 17 beta estradiol, 1.5 mg daily, or an equivalent dose by patch or orally, on a continuous basis. OUTCOME MEASURES: Menstrual pattern, endometrial histology and ultrasonographic evidence of endometrial suppression, after 3 years of use. RESULTS: The endometrial histology specimen showed profound endometrial suppression with glandular atrophy and stroma decidualization in all women. On transvaginal ultrasound, this corresponds with a thin endometrium (<5 mm) and clinically with a "bleed-free" menstrual pattern or amenorrhoea. CONCLUSION: The results of this 3-year study in 24 postmenopausal women using EST suggest that the FibroPlant-LNG IUS is effective in causing strong suppression of the endometrium during the entire period of EST. Target delivery in the uterine cavity could be the preferred route of administering a progestin to oppose estrogen stimulation of the endometrium.     

Intrauterine release of progesterone antagonist ZK230211 is feasible and results in novel endometrial effects: a pilot study

BACKGROUND: Continuous administration of progesterone antagonists (PAs) results in endometrial suppression and amenorrhoea in several model systems. We compared the effects of intrauterine release of a highly specific PA, ZK230211, to those of a progestin using the levonorgestrel-releasing intrauterine system (LNG-IUS). METHODS: Forty-two women were randomly fitted with an IUS releasing either ZK230211 at a rate 1, 4 or 8 microg/24 h (ZK-IUS) or LNG (at 20 microg/24 h, LNG-IUS) at 4-8 weeks before hysterectomy. Bleeding patterns, endometrial morphology and content of ZK230211, and various immunohistochemistries (IHCs) were evaluated. RESULTS: Days of bleeding and spotting were unchanged by the use of ZK-IUSs but were increased by LNG-IUS (P < 0.01). ZK230211 was measurable in all endometrial specimens. Endometrium was partly suppressed in 9-30% of women following the use of ZK-IUSs, and in 67% after LNG-IUS. IHCs for Ki-67 and phosphorylated histone H3 were not suggestive of proliferative activity in any group. Compared to LNG, progesterone receptor (PR) was increased following ZK230211 in surface epithelium (all three doses P < 0.01-P < 0.05) and stroma at 4 microg/24 h (P < 0.05). Although low, androgen receptor staining was higher in endothelial epithelium following LNG than ZK230211 (P < 0.05). Insulin-like growth factor-binding protein-1 (IGFBP-1) was detectable only following LNG (P < 0.0001). CONCLUSIONS: Short-term intrauterine release of ZK230211 did not change bleeding patterns or result in endometrial suppression. Expression of proliferation markers was low following the use of both IUSs. Absence of IGFBP-1 and increase in PR reflect the PA effects of ZK230211.     

Progestin receptor isoforms and prostaglandin dehydrogenase in the endometrium of women using a levonorgestrel-releasing intrauterine system

This study has examined endometrial tissue in 14 normal women prior to insertion of a levonorgestrel-releasing intrauterine system (LNG-IUS) and thereafter longitudinally for up to 12 months post-insertion. The specific endpoints examined by immunohistochemistry were progesterone receptor (PR) subtypes A + B, oestrogen receptor (ER) and prostaglandin dehydrogenase (PGDH). Two antiprogesterone receptor antibodies, one specific to PR(B) subtype and the other to PR subtype A + B, were employed to examine the localization of both PR isoforms. The activity of PGDH, a progesterone dependent enzyme, was also measured. ER and PR(A+B) and PR subtype B were significantly down-regulated in glands and stroma in the presence of continuous intrauterine LNG delivery. There was an apparent increase in PR(A) immunoreactivity in endometrial glands between 6 and 12 months post-insertion. Consistent with down- regulation of both isoforms of PR was reduced glandular PGDH immunostaining following LNG-IUS insertion, and PGDH activity (as measured by metabolism of excess substrate in vitro). Furthermore, PGDH activity, known to be localized in the glands, significantly increased (P < 0.05) at 12 months post-insertion, coinciding with the observed increase in glandular PR(A+B) immunoreactivity at this time. Since the LNG-IUS suppresses the PR(B) so strongly, PR(A) is likely to be the subtype that mediates long term LNG action in the endometrium. PR(B) is the more suppressed of the two subtypes, and only PR(A) rises along with PGDH activity. Alterations to normal endometrial morphology and function, e.g. perturbation of normal sex steroid receptor expression, following exposure to high concentrations of local LNG, may play a role in the aetiology of bleeding disorders associated with the LNG-IUS. Further elucidation of local uterine mediators involved in the mechanism of bleeding problems is required.      

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.     

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.     

Immunohistochemical estrogen receptor assessment in hyperplastic, neoplastic, and physiologic endometria

Endometrial hyperplasias and some endometrial carcinomas arise in a setting of estrogen excess. Steroid hormones interact with cells via specific receptors; assessing receptor levels may indicate a tissue's potential for interaction with that hormone. To examine estrogen receptor (ER) levels in endometrial hyperplasia, endometrial carcinoma, and physiologically cycling endometrium, an immunohistochemical technique utilizing a monoclonal anti-estrophilin (estrogen receptor) antibody was applied to formalin-fixed, paraffin-embedded tissue. In complex hyperplasia and grade I adenocarcinoma, the mean percentages of epithelial cells demonstrating nuclear staining for ER was mildly decreased compared to proliferative endometrium. A trend was noted toward less ER staining in atypical hyperplasia compared to non-atypical complex hyperplasia. ER varied with physiologic cycling of the endometrium. ER was also present in atrophic endometrium, myometrium, adenomyosis, and leiomyomata. Immunohistochemistry permits localization of ER and is a useful technique in ER assessment of endometrial hyperplasias and carcinomas.     

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.     

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.     

Oxidative stress in endometrial hyperplasia

OBJECTIVE: Reactive oxygen species seem to be involved in the onset and promotion of carcinogenesis. In 80% of cases of endometrial adenocarcinoma type I, a clear association exists with endometrial hyperplasia, which is considered a key factor in the endometrial oncological spectrum. The presence or absence of atypical cells determines oncological potential. This study explored the behavior of oxidative stress (catalase and malondialdehyde) in endometrial hyperplasia (with or without atypical cells) by comparing it with the oxidative stress existing in both the proliferative and secretory phases. DESIGN: Endometrial specimens from 55 women were used, 32 of which were histologically diagnosed as physiological (17 proliferative and 15 secretory endometria) and 23 as endometrial hyperplasia (18 nonatypical and 5 atypical endometrial hyperplasia). RESULTS: Significant differences were found in the malondialdehyde variable between the proliferative endometrium and the endometrium with atypical hyperplasia (P = 0.0208) and between both types of endometrial hyperplasia (P = 0.0441). The other comparisons were not statistically significant. No changes in catalase activity were observed. CONCLUSION: Our findings seem to suggest that the presence of atypical cells in endometrial hyperplasia induces a reduction in lipid peroxidation, which could permit survival and growth of these cells. This possible decrease in lipid peroxidation does not seem to be mediated by an increase in endometrial catalase activity.     

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.     

Hysteroscopy for asymptomatic postmenopausal women with sonographically thickened endometrium

Endometrial carcinoma is the most common genital cancer in women. While patients usually present with vaginal bleeding, in 10–20% this characteristic symptom is absent. Endometrial thickness (double layer) is measured by transvaginal sonography and thickening indicates an increased risk of malignancy or other pathology (hyperplasia or polyps). Objective: We sought to correlate hysteroscopic and pathological findings in asymptomatic postmenopausal women with sonographically thickened endometrium (>6 mm). Study design: A prospective observational study in a university hospital of 304 postmenopausal women referred between 1996 and 2006 because of a sonographically thickened endometrium in the absence of abnormal bleeding, who underwent continuous flow hysteroscopy (4.5 mm Storz hysteroscope) and fractionated curettage of the uterine cervix and corpus (D & C) in addition to vaginal sonography (5 MHz probe). Results: The mean age of the women was 64.8 (range 57.7–71.9) years. Average endometrial thickness measured by ultrasound was 12 mm ± 6.7 mm. Hysteroscopy suggested the presence of endometrial polyps in 226 women (74.3%), simple endometrial hyperplasia in 34 (11.2%), atrophic endometrium in 18 (5.9%), complex endometrial hyperplasia in 2 (0.7%), atypical hyperplasia in 3 (1%) and leiomyoma in 9 (3.0%). In 12 women (3.9%), the hysteroscopic appearance suggested malignancy and histology revealed endometrial adenocarcinoma. All hysteroscopic results were confirmed by histological examination. Conclusion: Hysteroscopy represents an easy, safe and effective method for the investigation of asymptomatic women with a thickened endometrium found with transvaginal ultrasound. The commonest pathology was endometrial polyps.