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.     

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.     

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.     

Performance and acceptability of intrauterine release of levonorgestrel with a miniature delivery system for hormonal substitution therapy,contraception and treatment in peri and postmenopausal women

OBJECTIVE: To evaluate the performance and acceptability of a novel intrauterine drug delivery system, FibroPlant-levonorgestrel (LNG), delivering approximately 14 microg per day. SUBJECT AND DESIGNS: A 1-year prospective clinical trial in 141 peri and postmenopausal women, including women with heavy or postmenopausal bleeding and women needing contraception. The majority received percutaneous 17beta-estradiol (Oestrogel), 1.5 mg daily. Clinical results and ultrasonographic effects were evaluated. RESULTS: Eighty-three insertions were done in perimenopausal women and 58 in postmenopausal women followed-up for 8-38 months. Fifty-two perimenopausal (64%) and virtually 100% of the postmenopausal women developed amenorrhoea, with occasional slight spotting. Eleven women with heavy bleeding, five of them with single or multiple intramural and subserosal fibroids of 3-6 cm or more, were all successfully treated, except one. There were no pregnancies. CONCLUSION: This study of 1432 women-months of use suggests that the frameless FibroPlant-LNG IUS is safe, well tolerated and effective in suppressing the endometrium during EST. The fact that the IUS also acts as a contraceptive, and significantly reduces menstrual bleeding, as demonstrated in earlier studies, is of added importance.     

Management of patients with non-atypical and atypical endometrial hyperplasia with a levonorgestrel-releasing intrauterine system: long-term follow-up

OBJECTIVES: Levonorgestrel (LNG), delivered locally into the uterine cavity has a profound effect on the endometrium. The aim of the study was to use a LNG intrauterine system to treat non-atypical and atypical endometrial hyperplasia in women and to evaluate the long-term cure (remission) rate. METHODS: Each of the 20 women in the study, of whom eight were diagnosed with atypical hyperplasia, received a LNG-IUS, releasing 20 microg LNG/day. The study is a non-comparative study with long-term follow-up (range 14-90 months). RESULTS: All women developed a normal endometrium, except one asymptomatic woman with atypical hyperplasia who still had focal residual non-atypical hyperplasia at 3 years follow-up in the presence of a thin (< 4 mm) endometrium. CONCLUSION: Continuous intrauterine delivery of LNG appears to be a promising alternative to hysterectomy for the treatment of endometrial hyperplasia and could enhance the success rate when compared with other routes of progestagen administration as well as intrauterine progesterone delivery. The significant reduction of the PR expression observed during treatment with the LNG-IUS appears to be a marker for the strong antiproliferative effect of the hormone at a cellular level resulting in an inhibition of estrogen bioactivity and endometrial suppression.     

The ultrastructure of human endometrium is altered by administration of intrauterine levonorgestrel

We studied the effect of intrauterine administration of levonorgestrel (LNG) on the ultrastructure of the endometrium. Twenty-one endometrial biopsy specimens, collected from nine fertile women during normal menstrual cycles and after 1, 3 or 6 months of use of a levonorgestrel- releasing intrauterine contraceptive system (LNG IUS), were studied using transmission and scanning electron microscopy. During the 6 month exposure to LNG IUS, changes took place in the endometrium. The glandular epithelial cells became lower. The junctional complexes between epithelial cells remained unchanged, whereas the lateral microvillar interdigitations became more prominent. The basal lamina under the epithelium became wavy but remained uniform and practically uninterrupted; only solitary epithelial cell protrusions through the basal lamina were seen. The stromal cells were largely decidualized. We conclude that in parallel with the generally known cellular effects, the use of the LNG IUS results in distinct changes in the basal lamina between the endometrial epithelial and stromal cells. The especially well-developed and uninterrupted basal lamina may be involved in the mechanism of the LNG IUS-induced endometrial suppression. Furthermore, the complex intercellular junctions between the epithelial cells, normally loosening around the time of implantation, persist during the local administration of levonorgestrel. This may have a pivotal role in the contraceptive effect of the LNG IUS.      

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.     

A simple method for determining the optimal dosage of progestin in postmenopausal women receiving estrogens

Progestin is often added to regimens of estrogen therapy in postmenopausal women to reduce the risk of endometrial hyperstimulation, but it may cause undesirable metabolic effects. Therefore, a low dosage is recommended. At present, the only way to determine whether the dosage of progestin is causing the desired secretory transformation of the endometrium is by endometrial sampling, which is invasive. We studied 102 postmenopausal women undergoing estrogen therapy who also took a progestin for 12 days each month, and we correlated the day of onset of bleeding with the endometrial histology over a three-month period. A bleeding pattern suitable for interpretation was observed in 96 women. Regardless of the preparation and dosage of the estrogen and progestin used, wholly or predominantly proliferative endometrium was always associated with bleeding on or before day 10 after the addition of progestin; wholly or predominantly secretory endometrium, or a lack of endometrial tissue, was associated with bleeding on day 11 or later. We conclude that the bleeding pattern reflected the histologic condition of the endometrium and that adjustment of the dosage of progestin so that regular bleeding is induced on or after day 11 may obviate the need for endometrial biopsy.     

Cyclooxygenase-2 expression in the endometrium at the end of 2 years' continuous combined hormone replacement therapy

Objective: To evaluate the change of endometrial histology and the expression of cyclooxygenase-2 (Cox-2) in the endometrium after continuous combined hormone replacement therapy (HRT). Methods: Forty-five postmenopausal women were recruited. All participants received 0.625 mg conjugated equine estrogen (CEE) and 2.5 mg medroxyprogesterone (MPA) daily for 2 years. Endometrial biopsy was performed twice, before medication (baseline) and after 2 years of HRT, respectively. Immunohistochemistry was used to detect the presence of Cox-2 expression. Results: More atrophic and weak secretory features of endometrium were noted after the 2-year HRT. Endometrial hyperplasia and carcinoma were not found and immunohistochemistry results revealed that Cox-2 was not expressed in the endometrium. Conclusion: Cox-2, known to play an important role in the tumorigenesis of cancer, was not stained in endometrium tissue after hormonal induction and more endometrium atrophy was noted after the 2-year HRT. From the results, it is noted that continuous combined HRT may be a relatively safe and appropriate regimen for long-term use in postmenopausal women.     

Endometrial assessment in women using tibolone or placebo: 1-year randomized trial and 2-year observational study

OBJECTIVE: To assess the effects of tibolone on the endometrium of postmenopausal women. DESIGN: A 1-year randomized, double-blind, placebo-controlled clinical trial and a 2-year open clinical trial. The placebo-controlled trial included 40 participants: 20 in the placebo group and 20 in the tibolone group; in the open trial, 17 participants receiving tibolone were assessed over 24 months. Transvaginal ultrasonography was carried out to assess endometrial thickness, and endometrial appearance was assessed on hysteroscopy. In addition, endometrial samples were submitted to histological examination. The occurrence of uterine bleeding and other adverse effects was also assessed. RESULTS: Results suggest that tibolone does not exert a stimulatory effect on the endometrium: unaltered endometrial thickness, atrophic appearance of most endometria on hysteroscopy, and endometrial histology classified as atrophic, hypotrophic with incipient secretion, or hypotrophic with weak proliferation (one case). Tibolone was effective in the treatment of climacteric symptoms, and only 8.7% of the participants presented uterine bleeding during treatment. CONCLUSIONS: Tibolone seems to be an effective option for the treatment of climacteric symptoms in postmenopausal women, especially in women who do not want to experience uterine bleeding again.     

A comparative study of transvaginal uterine ultrasound and endometrial biopsy for evaluating the endometrium of postmenopausal women taking hormone replacement therapy.

OBJECTIVE: Compare transvaginal uterine ultrasound and endometrial biopsy in evaluating the endometrium of postmenopausal women who are taking estrogen replacement therapy (ERT) or hormone replacement therapy (HRT; estrogen and progestin). DESIGN: Prospective multicenter study done in the United States with 148 healthy women with an intact uterus. A total of 121 women used hormonal preparations prescribed by personal physicians. Continuous combined HRT regimens, nonoral forms of ERT or HRT, and intrauterine devices were not allowed for 3 months before the study began. Endometrial biopsy samples were taken within 3 days of transvaginal ultrasound measurement. The uterus was scanned transversely and longitudinally. Endometrial thickness was measured at the thickest part of the longitudinal plane. RESULTS: Endometrial thickness ranged from 1.0 to 25.0 mm. The range in 126 women with a normal endometrium (determined by diagnoses of endometrial biopsies) was 1.0-25.0 mm (median, 5.0 mm); in 15 women with an abnormal endometrium, the range was 2.8-23.0 mm (median, 6.2 mm). A significant difference (p = 0.006) in endometrial thickness was seen between the 38 subjects taking ERT and HRT (median, 6.1 mm) with unexpected bleeding or spotting and the 26 untreated women in the control group (median, 4.0 mm). Overall, results were clinically inconclusive. CONCLUSIONS: Results of ultrasound as a screening technique in postmenopausal women who were taking ERT or HRT did not correlate well with results of endometrial biopsy. Unscheduled bleeding in postmenopausal women should be investigated regardless of results of ultrasonographically determined endometrial thickness. Abnormalities may be found with an endometrial thickness of less than 4 mm with or without HRT and even with no bleeding.     

Hormonal replacement regimens and bleeding

Hormone replacement therapy may increase the quality of life of postmenopausal women. Any regimen need to offer long-term endometrial safety. It is a standard to consider the co-administration of a sequential progestogen when estrogen replacement should be initiated in non-hysterectomized women. It is almost impossible to decide which combination of an estrogen and a progestogen seems to be optimal as individual tolerance of HRT may very well limit acceptability despite metabolic benefits and proven endometrial safety of a given combination. Several combinations of oral and transdermal estradiol or conjugated equine estrogens, oral progestogens, transdermal norethisterone acetate and levonorgestrel, and intrauterine levonorgestrel may achieve endometrial safety. It is noteworthy that there is no uniform correlation between the timing of onset of bleeding induced by any sequential estrogen and progestogen replacement and a certain pattern of histology. Therefore, although it is likely, there is no absolute reassurance that regular bleeding on or after day 11 of progestogen administration rules out abnormal histopathology. Transvaginal sonography seems not to be of pivotal importance to screen asymptomatic women on replacement therapy for detection of serious abnormal endometrial findings such as hyperplasia and endometrial cancer. Continuous combined hormone replacement therapy or the use of tibolone may be an alternative in postmenopausal women, who do not want any uterine bleedings after menopause. However, spottings or bleedings most often occur at the beginning of treatment. Vaginal administration of estriol and estradiol for urogenital symptoms of estrogen deficiency may stimulate the endometrium unintentionally. Available data suggest that use of oral estriol may be associated with endometrial hyperplasia and endometrial carcinoma relatively more often compared to sequential HRT. Raloxifene, a benzothiophene derivative acting as a selective estrogen receptor modulator approved for prevention of vertebral osteoporosis, rarely causes uterine bleeding. There is no ideal therapy available to suit women looking for a permanently bleed-free hormonal replacement therapy today.     

The prevention of endometrial cancer in postmenopausal women with progestogens

Due to adverse publicity alleging an increased risk of endometrial cancer with estrogen therapy, a prospective study was begun in 1976 to determine the incidence of this disease in postmenopausal women. During 5,025 patient-years of observation in 1976–1977, 6 adenocarcinomas of the endometrium were diagnosed for an incidence of 1.2: 1,000 postmenopausal women per year. No endometrial malignancies were detected in 2,552 patient-years of therapy with estrogens and progestogens. In 1,028 patient-years of observation where estrogens only was the therapy, there were 3 endometrial cancers for an incidence of 2.9: 1,000. Adenocarcinoma of the endometrium was found in 2 of the untreated group, which gave an incidence of 3.0: 1,000. The sixth endometrial cancer occurred in a patient using estrogen vaginal cream. During this same period, 139 perimenopausal and postmenopausal women were treated with progestogens for endometrial hyperplasia. The hyperplasia was reversed to normal endometrium in 133 patients (95.7%). Hyperplasia is a precancerous lesion and should be treated with either progestogens or hysterectomy. All postmenopausal women with a uterus should be given the Progestogen Challenge Test and the progestogen continued each month as long as bleeding follows. These methods will prevent most endometrial cancers.     

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.     

Immunohistochemical expression of estrogen and progesterone receptors in endometrial polyps and adjacent endometrium in postmenopausal women

OBJECTIVE: To detect the presence of estrogen (ER) and progesterone (PR) receptors in endometrial polyps and adjacent endometrium in postmenopausal women. METHODS: Forty-four consecutively enrolled postmenopausal patients were submitted to operative hysteroscopy. These patients had diagnosed benign endometrial polyp. The presence of ER and PR was determined in endometrial samples and polyps by immunohistochemical method and the slides were evaluated using a semiquantitative analysis. RESULTS: In the glandular epithelium, the median of the ER score was 7.0 in the polyps and 5.0 in the endometrium (P<0.0001) and the median of the PR was 6.0 in the polyps and 4.0 in the endometrium (P<0.0001). In the stroma, the median of the ER score was 6.0 in the polyps and 5.0 in the endometrium (P=0.021) and the median of the PR score was 4.0 in the polyps and 4.5 in the endometrium (P=0.34 ). CONCLUSIONS: Our data suggests that steroids receptors present a crucial role in the phisiopathology of the endometrial polyps in postmenopausal women, specially the estrogen receptors.     

Intra-uterine fluid collection in postmenopuasal women with cervical stenosis

OBJECTIVES: The aim of the study was to assess the clinical significance of intra-uterine fluid collection in postmenopausal women with cervical stenosis with and without vaginal bleeding. METHODS: A group of 82 consecutive postmenopausal women with cervical stenosis and sonographically confirmed intra-uterine fluid collection underwent D&C with or without hysteroscopy. Diagnostic hysteroscopy was performed in all patients with an endometrial thickness (ET) was greater than 8mm, or with irregular endometrium at any degree of ET. The patients were divided and evaluated prospectively into two groups according to the presence or absence of postmenopausal bleeding (PMB). Twenty-six women were with PMB and 56 women were asymptomatic. RESULTS: The groups were similar as far as endometrial thickness and histopathological results were concerned. Atrophic endometrium was found in 69 patients (84%), 23 in the PMB group (89%) and 46 in the other group (82%), proliferative endometrium in 7 (9%) and endometrial polyps were found in 35 patients (43%), 12 in the PMB group (46%) and 23 in the other group (41%). When ET was > or =8 mm, in 93% of the cases an endometrial polyp was found (25 out of 27). No case of endometrial cancer was found. A premalignant condition was diagnosed in one patient with an endometrial polyp in the PMB group. All patients with endometrial thickness of less than 3 mm in ultrasound had atrophic endometrium. The incidence of intrauterine pathology increased with the increasing thickness of endometrium as observed by ultrasound. CONCLUSIONS: The presence of intra-uterine fluid collection in postmenopausal patients with cervical stenosis seems to be a benign condition. Normal endometrium of less than 3mm observed by ultrasound in postmenopausal women without vaginal bleeding does not necessarily need further surgical investigation.     

Changes in the withdrawal bleeding pattern and endometrial histology during 17β-estradiol —dydrogesterone therapy in postmenopausal women: a 2 year prospective study

Objective: To describe changes in the withdrawal bleeding pattern and endometrial histology during a sequential 17β-estradiol —dydrogesterone regimen in postmenopausal women. Design: Open-label, non-comparative, prospective study. Setting: Gynecological outpatient department of a university hospital. Patients: Twenty-seven healthy nonhysterectomized postmenopausal women. Interventions: Continuous micronized 17β-estradiol supplementation, 2 mg daily, and cyclic administration of dydrogesterone, 10 mg daily for the first half of each 28 day treatment cycle. Main Outcome Measures: Changes in the characteristics of the withdrawal bleeding pattern and the endometrial biopsy histology during 2 years of treatment. Results: The initial withdrawal bleeding was comparable to normal menstruation with respect to amount and duration. During the 2 years of treatment the bleeding showed a significant tendency to become shorter with less blood loss. This was mainly the result of the decrease (P < 0.001) in the number of days per cycle with bleeding grade II (normal menstruation). None of the women developed endometrial hyperplasia, and in almost all women the given hormone replacement therapy regimen induced secretory or atrophic changes of the endometrium. Conclusions: This sequential 17β-estradiol —dydrogesterone regimen can be regarded as safe with respect to the prevention of endometrial disease and appeared to foster patient compliance.     

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.     

Effects of testosterone and estrogen treatment on the distribution of sex hormone receptors in the endometrium of postmenopausal women

OBJECTIVE: Our aim was to investigate the effects of the addition of testosterone to estrogen compared with those of estrogen alone on the expression and distribution of sex hormone receptors in glands and stroma of the endometrium of postmenopausal women. DESIGN: An open, randomized clinical study with parallel group comparison was performed in the Women's Health Research Unit at a university hospital. Thirty-one postmenopausal women were given oral estradiol valerate (2 mg daily) or estradiol valerate in combination with testosterone undecanoate (40 mg every 2 days) for 3 months. Before and at the end of treatment, endometrial biopsy samples were obtained, and expressions of estrogen receptor (ER)-alpha, ER-beta, progesterone receptor isoforms A and B, and androgen receptor (AR) were evaluated by immunohistochemical analysis. RESULTS: At baseline, expressions of ER-alpha and progesterone receptors were stronger in glands than in stroma, whereas the immunostaining of AR was stronger in stroma than in glands. After treatment, expressions of ER-alpha and progesterone receptors were up-regulated in both glands and stroma by both treatments, but to a lesser extent in glands by combined treatment. The expression of ER-beta in glands was significantly higher with combined treatment than with estrogen alone. Moreover, AR immunostaining was significantly higher after combined treatment than after treatment with estrogen alone. CONCLUSIONS: Expressions of AR and ER-beta were stronger in glands of the endometrium of postmenopausal women after treatment with testosterone added to estrogen than after estrogen alone. In contrast, expressions of ER-alpha and progesterone receptors were up-regulated in the endometrium with estrogen-alone treatment, whereas these expressions were less increased in glands after combined treatment. These data indicate that testosterone is involved in the regulation of sex hormone receptor expression in the postmenopausal endometrium and may therefore influence endometrial proliferation and differentiation.