Expression of the chemokines, monocyte chemotactic protein (MCP)-1 and MCP-2 in endometrium of normal women and Norplant users, does not support a central role in macrophage infiltration into endometrium.

The endometrium contains many leukocytes, including macrophages, the numbers varying with the time of the menstrual cycle and being maximal peri-menstrually. The long-acting progestogenic contraceptive Norplant, has a high rate of discontinuation due to uterine bleeding; this is associated with large numbers of endometrial macrophages. Monocyte chemotactic proteins (MCP) act to recruit and activate monocytes into sites of inflammation. This study compared the cellular localization of endometrial MCP-1 and MCP-2 across the normal menstrual cycle and in users of Norplant. Both MCP-1 and MCP-2 were present in normal endometrium, but with very different patterns of cellular location and considerable variability between individuals. MCP-1 of epithelial origin was present in 77% of tissues, while stromal staining was present in 52% and vascular staining in 34% of samples. MCP-1 was also released from both epithelial and stromal cells in culture. MCP-2 staining was predominantly epithelial and was found in 52% of tissues while stromal staining was present in only 3/56 samples. Vascular staining of MCP-2 was found in 2/56 samples. The epithelial staining was mostly punctate and sometimes within uterine secretions. No correlation of staining for MCP-1 or -2 with the phase of the cycle was found in any cellular compartment. Very little immunoreactive MCP-1 or MCP-2 was detected in endometrium from Norplant users regardless of morphological subtype. These distributions do not support a role for either MCP-1 or MCP-2 in the migration of macrophages into the endometrium and suggest that these cytokines may have other functions in this tissue.

Training for Norplant implant removal: assessment of learning curves and competency.

OBJECTIVE: To determine the learning curves and rapidity with which clinicians become competent in implant removal using two Norplant removal techniques. METHODS: Twenty-four physicians, none of whom were experienced in the use of Norplant implants, were randomly assigned to learn either the "U" removal technique or the standard technique. The physicians in the two groups received identical training in all other respects. Each physician then performed ten supervised removals. Removal times, procedure problem rates, and the number of procedures performed by the clinicians before they were judged "competent" were assessed for both groups. RESULTS: Data from 240 removals were analyzed. Mean removal times were 38% faster in the "U" group than in the standard group. None of the "U" group procedures took longer than 20 minutes, compared with 11% of removals in the standard group (P < .001). The mean number of cases required before the provider consistently performed all steps adequately was significantly (P < .02) higher in the standard group (5.8 cases) than in the "U" group (3.9 cases). CONCLUSIONS: Using competency-based training methods, the "U" removal technique was learned easily by inexperienced clinicians. It appears to offer significant improvements in speed and achievement of proficiency over the standard technique recommended by the manufacturer. Large-scale programs should consider using competency-based training and the "U" technique as the removal method of choice when providing training in implant removal.

Endometrial expression of glycodelin in women with levonorgestrel-releasing subdermal implants.

OBJECTIVE: To determine whether subdermal levonorgestrel implants induce endometrial expression of glycodelin. DESIGN: Cross-sectional, blinded study. SETTING: University clinic. PATIENT(S): One hundred and eight women with subdermal implants and 19 postmenopausal women. INTERVENTION(S): Endometrial biopsies, curettages, and hysterectomies. MAIN OUTCOME MEASURE(S): Endometrial glycodelin expression was examined through immunohistochemistry, in situ hybridization, and morphologic endometrial dating. RESULT(S): Overall, 80% of the endometrial specimens obtained from women with subdermal levonorgestrel implants stained positive for glycodelin. Endometrial morphology of these women showed proliferative (71%), inactive/weakly proliferative (19%), menstrual or regenerating (6.5%), and other patterns (2.8%). Of these, 79%, 71%, 100%, and 100% were glycodelin positive, respectively. Nineteen specimens were obtained during the midcycle when glycodelin is not normally expressed: of these, 89% stained positive for glycodelin. Implant-related amenorrhea was associated with endometrial glycodelin expression in 58% of the women, whereas the endometrium specimens obtained from women with postmenopausal hypoestrogenic amenorrhea contained no detectable glycodelin. CONCLUSION(S): Subdermal levonorgestrel implant use is often associated with endometrial expression of glycodelin. Because glycodelin has been shown to inhibit sperm-egg binding, the induction of glycodelin may contribute to the contraceptive activity of the implant.

Benefits of vitamin E supplementation to Norplant users--in vitro and in vivo studies.

Norplant subcutaneous implantation is a contraceptive method used in Indonesia. Endometrial bleeding is one major reason to discontinue the use of Norplant. Angiogenic response in the endometrium of Norplant users was found to be lower than in women with normal menstrual cycle. This disturbance in the angiogenic process may be caused by an imbalance of pro- and antioxidant processes in the endometrium of Norplant users. The aim of this study is to investigate the effect of vitamin E on the endometrial angiogenic activity and to assess the efficacy of vitamin E supplementation in treating endometrial bleeding in Norplant users. Subjects for this study were selected from Norplant users with an exposure of at least 3 months, with endometrial bleeding and recruited on the basis of fully informed consent. TBA reaction was used to measure degradation products of lipid peroxidation. The endometrial angiogenic response was assayed according to Folkman et al. (Folkman et al., 1989. Nature 239, 58-61). Samples from endometrial biopsies were incubated in vitro with vitamin E or placebo before angiogenic measurement. For in vivo supplementation, vitamin E 200 mg/day, or placebo for 10 days/month were given to the subjects with double blind randomisation. The results showed that the blood levels of TBA-reactive substances were significantly higher in Norplant users than in controls. In the endometrium from Norplant users with bleeding problems, in vitro supplementation of vitamin E resulted in a significantly higher angiogenic score than placebo. Although a highly significant reduction of bleeding days in both groups, vitamin E and placebo, was seen during the 2 months of the study, the number of bleeding days was significantly lower in women treated with vitamin E than with placebo.

An integrated analysis of vaginal bleeding patterns in clinical trials of Implanon.

The vaginal bleeding patterns observed during the use of the single-rod progestin-only implant, Implanon, compared with those seen during the use of the six-capsule implant, Norplant, have been analyzed. The acceptability of these bleeding patterns was also assessed. An integrated analysis of 13 different trials was done, studying reference periods (RP) of 90 days. These trials included totals of 1716 Implanon users and 689 Norplant users. There were statistically significant lower mean values over RP 2-8 the range over RP 2-8 is presented) for Implanon, for the number of bleeding-spotting days (15.9-19.3 vs 19.4-21.6; p = 0.0169), the number of bleeding days (7.5-10.0 vs. 11.7-13.1; p < 0.001), and the number of bleeding-spotting episodes (2.2-2.7 vs. 3.1-3.3; p < 0.0001). The bleeding patterns of Implanon users appeared to be more variable than those observed with Norplant: Implanon users had more amenorrhea, and slightly more infrequent bleeding, frequent bleeding, and prolonged bleeding than Norplant users. The difference was only statistically significant for amenorrhea (17.9%-24.8% with Implanon compared with 2.0%-7.0% for Norplant over RP 2-8). There were no statistically significant differences in the acceptability of the two products as indicated by the discontinuation rates, which were 30.2% and 0.9% in Europe and Southeast Asia, respectively, for Implanon, and 22.5% and 1.4%, respectively, in the two regions, for Norplant. The individual bleeding pattern was not predictable. However, in general, it can be stated that women initially without bleeding or with infrequent bleeding have only a small chance of becoming frequent bleeders, and vice versa. Dysmenorrhea clearly improved during use of both Implanon and Norplant. Neither Implanon nor Norplant caused anemia.

The effects of Implanon on lipid metabolism in comparison with Norplant.

This open, randomized study was intended to assess the effects of the new single-rod contraceptive implant (Implanon) containing etonogestrel on lipid metabolism in Indonesian women, in comparison with the six-rod implant Norplant, containing levonorgestrel. The effects of both products were compared with a control group using an intrauterine device (IUD) over a 3-year period. A total of 135 healthy volunteers of childbearing potential, aged 22 to 41 years, were enrolled in Jakarta, Indonesia. Ninety volunteers were randomized to use Implanon (n = 45) or Norplant (n = 45), and a nonrandomized group of 45 Multiload Cu 250 IUD users served as a control. Serum concentrations of total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, apolipoprotein AI, apolipoprotein AII, and apolipoprotein B were measured. The ratios of HDL cholesterol to total cholesterol, of HDL to LDL cholesterol, and of apolipoprotein AI to apolipoprotein B were determined. Lipid and lipoprotein determinations were done at screening and after 3, 6, 12, 18, 24 and 36 months. Contraceptive efficacy and insertion and removal times were also recorded. Mean changes from baseline in the lipid and apolipoprotein parameters, although occasionally statistically significant, were small in all groups (less than 1 standard deviation of the mean concentration at baseline) and clinically not significant. Statistically significant differences between the Implanon and Norplant groups were only occasionally observed. In both implant groups, total mean cholesterol, LDL cholesterol, and apolipoprotein AI concentrations tended to decrease during the study, but statistically significant changes from baseline were only occasionally observed, suggesting that drug-related factors are not involved. The mean ratios of HDL/total cholesterol and the HDL/LDL cholesterol showed very little change over time in both implant groups; slight and statistically nonsignificant increases were noted at most time points. Similar changes were seen in the group of IUD users. It can be concluded that changes from baseline in the lipid and apolipoprotein parameters tested were generally small and did not differ between Implanon and Norplant.

PIP: This open, randomized study was intended to assess the effects of the new single-rod contraceptive implant (Implanon) containing etonogestrel on lipid metabolism in Indonesian women, in comparison with the six-rod implant Norplant, containing levonorgestrel. The effects of both products were compared with a control group using an IUD over a 3-year period. A total of 135 healthy volunteers of childbearing potential, aged 22 to 41 years, were enrolled in Jakarta, Indonesia. 90 volunteers were randomized to use Implanon (n = 45) or Norplant (n = 45), and a nonrandomized group of 45 Multiload Cu 250 IUD users served as a control. Serum concentrations of total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, apolipoprotein AI, apolipoprotein AII, and apolipoprotein B were measured. The ratios of HDL cholesterol to total cholesterol, of HDL to LDL cholesterol, and of apolipoprotein AI to apolipoprotein B were determined. Lipid and lipoprotein determinations were done at screening and after 3, 6, 12, 18, 24 and 36 months. Contraceptive efficacy and insertion and removal times were also recorded. Mean changes from baseline in the lipid and apolipoprotein parameters, although occasionally statistically significant, were small in all groups (less than 1 standard deviation of the mean concentration at baseline) and clinically not significant. Statistically significant differences between the Implanon and Norplant groups were only occasionally observed. In both implant groups, total mean cholesterol, LDL cholesterol, and apolipoprotein AI concentrations tended to decrease during the study, but statistically significant changes from baseline were only occasionally observed, suggesting that drug related factors are not involved. The mean ratios of HDL/total cholesterol and the HDL/LDL cholesterol showed very little change over time in both implant groups; slight and statistically nonsignificant increases were noted at most time points. Similar changes were seen in the group of IUD users. It can be concluded that changes from baseline in the lipid and apolipoprotein parameters tested were generally small and did not differ between Implanon and Norplant.

Immunohistochemical staining of von Willebrand factor in endometrium of women during the first year of Norplant implants use.

The mechanisms responsible for Norplant implants-induced menstrual irregularities remain poorly understood. It is unclear whether local changes in endometrial haemostasis are involved. The aim of the present study was to examine the immunohistochemical staining for von Willebrand factor (vWF) in endometrial biopsies taken from 37 women exposed to Norplant implants for 3-12 months and to compare it with 73 controls at various phases of the normal menstrual cycle. The vWF staining intensity was quantified by subjective scoring and by objective computerised colour image analysis. Results from the Norplant implants group were additionally correlated with their bleeding patterns, endometrial histology, and plasma oestradiol (E2) and progesterone (P4) levels. No differences were found between control and Norplant implants subjects in the localization of vWF staining, which was specifically confined to the endothelium of endometrial blood vessels. vWF staining intensity in Norplant implants endometrium was significantly lower than in controls during mid cycle, and reached a mean (+/- SE) level (subjective staining score 2.05 +/- 0.13, n = 37) in the range of the early proliferative and mid secretory phase normal endometrium; nevertheless, it remained significantly higher than that of menstrual and late secretory phase normal endometrium. No significant variations in vWF staining could be related to either the histology of the endometrium or the bleeding pattern of the users. Correlation of vWF staining with either serum E2 or serum P4 prior to biopsy, or to the number of days of Norplant implants exposure revealed no significant relationships. However, vWF staining was positively correlated (r = 0.419, P < 0.01) to the number of bleeding/spotting days within a 90-day reference period prior to biopsies being taken. These results demonstrate that there are major differences in the mechanism responsible for normal menstruation and Norplant implants-induced intermenstrual bleeding and spotting, and show that menstrual disturbances associated with the use of Norplant implants are unlikely to be due to changes in vWF levels in endometrial endothelial cells.

PIP: Changes in the bleeding pattern during women's menstrual cycle have been associated with Norplant subdermal contraceptive implants, which release levonorgestrel (LNG). This article reports the findings of a study on possible effects of LNG on endometrial hemostasis and coagulation, with particular emphasis on the von Willebrand Factor (VWF). Endometrial VWF was examined by immunohistochemical staining. 37 Indonesian women who were exposed to Norplant implants for 3-12 months were studied. Endometrial biopsies were taken during the 3-12 month period following insertion of the implant. Biopsies were taken using a microhysteroscope or a Pipelle suction curette. 73 Australian women with normal menstrual cycles served as controls in this study. Blood analysis was used for establishing baseline and subsequent hormone measurements. Of the 37 exposed women, 9 were classified as histopathologically atrophic, 11 as iatrogenic progestogenic, 4 as proliferative, 4 as secretory, and 9 as shedding. No significant differences were observed in the localization of VWF staining between implant-exposed and control groups. VWF immunostaining, correlated against the number of implant days exposed, showed no significant relationship (r = 0.054, P 0.01). Levels of VWF staining in the endometrium of Norplant users were significantly higher than those in women whose menstrual and late secretory phase endometrium were normal. Levels of VWF were lower than normal mid-cycle bleeding patterns. VWF levels are unlikely to be associated with observed menstrual disturbances.

A pilot efficacy study with a single-rod contraceptive implant (Implanon) in 200 Indonesian women treated for < or = 4 years.

In this 4-year open-label, noncomparative, single-center pilot efficacy study, the contraceptive efficacy, safety, bleeding pattern and acceptability of Implanon was studied in 200 sexually active women of proven fertility in Indonesia. All subjects received the single-rod subdermal implant Implanon, which contains 68 mg etonogestrel (3-keto-desogestrel), with an initial release rate of 67 micrograms etonogestrel/day. Contraceptive efficacy was analyzed by calculation of the pregnancy rate, bleeding patterns were determined by the 90-day reference period method, and acceptability by the discontinuation rate. No in-treatment pregnancies were reported during 658.4 women-years of exposure, resulting in a Pearl Index of 0.0 (95% CI 0.0-0.6). The overall bleeding pattern was acceptable, with no discontinuations because of irregular bleeding. Incidence of irregular bleeding was highest during the first two reference periods and decreased thereafter. Amenorrhea was experienced by 7%-12% of subjects during years 1 and 2, by 5%-7% during year 3, and by 2%-5% during year 4, with one discontinuation because of amenorrhea. No clinically significant changes were reported for systolic and diastolic blood pressure, body mass index, and hemoglobin level. Three adverse experiences were related to treatment and resulted in discontinuation (two headaches and one dyspnea). One difficult implant removal was reported. In conclusion, this pilot efficacy study indicates that Implanon provides excellent contraceptive reliability and an acceptable bleeding pattern. Overall safety and acceptability are good, as suggested by the low incidence of adverse experiences and the low discontinuation rate.

Cytokeratins 8, 18 and 19 in endometrial epithelial cells during the normal menstrual cycle and in women receiving Norplant.

Cytokeratins 8, 18 and 19 are members of the cytoskeletal intermediate filament protein family. They are expressed in all simple epithelial tissues, including endometrium, and are recognised as dynamic structures that can be affected by numerous external factors. The Norplant system is a subdermal slow release levonorgestrel implant commonly used as a long-acting progestogen contraceptive. Norplant implants have been shown to have atrophic effects on endometrial epithelial and stromal cells, and cause a range of endometrial bleeding problems among users. The aim of this study is to describe changes in the immunohistochemical expression and distribution of cytokeratins 8, 18 and 19 in endometrial epithelial cells of Norplant implants users and normal menstrual cycle controls. Endometrial biopsies were collected from 65 control normal cycle women and 37 Norplant implants acceptors. The normal menstrual cycle was classified histologically into 9 stages; one menstrual, five proliferative and three secretory. Norplant implants bleeding patterns were categorised into 6 groups according to current World Health Organisation (WHO) definitions; amenorrhoea, frequent bleeding, infrequent bleeding, irregular bleeding, "normal" bleeding, and prolonged bleeding. The tissues were fixed in formalin, embedded in paraffin, and stained immunohistochemically. Semi-quantitative scoring of the staining intensity was performed. Apical versus basal intracellular cytokeratin distribution was also evaluated. The staining intensity was significantly stronger in control endometrial tissue compared to Norplant implants tissue. In control tissues, cytokeratins were predominantly located in the apical region of epithelial cells (52% of biopsies) and in Norplant implants tissues they were predominantly distributed equally between the apical and basal portions of epithelial cells (43% of biopsies). There was no particular cytokeratin distribution pattern associated with the different stages of normal cycle or the different Norplant implants bleeding patterns. It was concluded that long-term exposure to levonorgestrel significantly reduced the cytokeratin expression in endometrial epithelial cells (P < 0.001).

PIP: Researchers compared endometrial tissue data on 37 women, 21-38 years old, in Jakarta, Indonesia, who were using Norplant contraceptive implants for 3-12 months with similar data on 65 women, 19-49 years old, in Melbourne, Australia, who had normal menstrual cycles and were not using any hormonal contraception or an IUD. They aimed to describe changes in the immunohistochemical expression and distribution of cytokeratins 8, 18, and 19 in endometrial epithelial cells of Norplant users and normal menstrual cycle controls. They also wanted to determine whether any levonorgestrel-induced changes in epithelial cytokeratin expression might effect structural fragility of the endometrium and thus contribute to endometrial bleeding. 26 cases experienced some type of prolonged bleeding pattern. There were no differences in cytokeratins 8, 18, and 19 immunostaining intensity between either the different stages of normal menstrual cycle or between different bleeding patterns among Norplant users. On the other hand, the cytokeratins of controls exhibited much greater immunostaining intensity (i.e., more cytokeratins 8, 18, and 19 in the endometrium) than Norplant users (staining score, 2.6 vs. 1.4; p 0.001). This effect may be associated with increased endometrial fragility that could result in increased bleeding. The cytokeratins in the biopsies belonging to the control group were mainly located in the apical region of epithelial cells (52%) while they tended to be evenly distributed in the apical and basal portions of epithelial cells in the Norplant group (43%). 14% of biopsies in the Norplant group did not stain for cytokeratins. No particular cytokeratin distribution pattern emerged with the various stages of the normal menstrual cycle or the various Norplant-related bleeding patterns. These findings show that levonorgestrel exposure decreases expression of cytokeratins 8, 18, and 19 in endometrial cells.

Serum lipids in Norplant implants users: a cross-sectional study.

One of the methods to establish the safety and risk profile of hormonal contraceptives is employing a study on their metabolic effects. In order to evaluate the effect of Norplant implants on serum lipids, a cross-sectional study was undertaken at Klinik Raden Saleh, Jakarta. The subjects recruited were divided into 8 groups depending on the length of Norplant use, i.e. before insertion, 6 months, 12 months, 24 months, 36 months, 48 months, 60 months and one week after the removal of Norplant. Blood samples were collected from the subjects after an overnight fast. The parameters studied were triglycerides, total cholesterol, HDL-cholesterol and LDL-cholesterol. There were no significant differences between the groups regarding the triglycerides and HDL-cholesterol (p greater than 0.05). There were significant differences between the groups regarding the total cholesterol and LDL-cholesterol (p less than 0.01).

The interaction between sex hormone binding globulin and levonorgestrel released from Norplant, an implantable contraceptive.

Two-hundred-and-eighty Indonesian women were provided with Norplant, a levonorgestrel-releasing implant. At various time intervals, up to 5 years after Norplant insertion, levonorgestrel and sex hormone binding globulin (SHBG) were assayed in blood plasma. After an initial burst of approximately 7 nmol/l, the levels of levonorgestrel rapidly decreased during the first month. The decrease continued to a nadir (1.1 nmol/l) which was reached 10 months later. The decrease was followed by an increase to a broad peak of 1.5 nmol/l which was reached 2 years after insertion. Thereafter, a slow-decrease at a rate of approximately 18 pmol/month was seen. SHBG levels decreased significantly already 1 week after insertion. A nadir of levels (25 nmol/l) was reached 3 months later. The levels increased slowly again and remained constant (32 nmol/l) from about 15 months to 5 years. During the entire period of study highly significant correlations of levonorgestrel with SHBG were seen. In another group of 25 women the levels of levonorgestrel and SHBG were studied before and one week after insertion of Norplant. A significant correlation (r = 0.77) was found between the preinsertion levels of SHBG and postinsertion levels of levonorgestrel.

PIP: 288 Indonesian women were provided with Norplant a levonorgestrel-releasing implant. At various time intervals, up to 5 years after Norplant (R) insertion, levonorgestrel and sex hormone binding globulin (SHBG) were assayed in blood plasma. After an initial burst of approximately 7 nmol/1, the levels of levonorgestrel rapidly decreased during the 1st month. The decrease continued to a nadir (1.1 nmol/1) which was reached 10 months later. The decrease was followed by an increase to a broad peak of 1.5 nmol/1 which was reached 2 years after insertion. Thereafter, a slow decrease at a rate of approximately 18 pmol/month was seen. SHBG levels decreased significantly already 1 week after insertion. A nadir of levels (25 nmol/1) was reached 3 months later. The levels increased slowly again and remained constant (32 nmol/1) from about 15 months to 5 years. During the entire peiod of study highly significant correlations of levonorgestrel with SHBG were seen. In another group of 25 women the levels of levonorgestrel and SHBG were studied before and 1 week after insertion of Norplant. A significant correlation (r=0.77) was found between the preinsertion levels of SHBG and postinsertion levels of levonorgestrel.

Five-year experience with Norplant.

At Klinik Raden Saleh, Department of Obstetrics and Gynaecology, University of Indonesia, from 1 May until 31 August, 1981, Norplant contraceptive implants were inserted into 437 Indonesian women. The continuation rates of Norplant at first, second, third, fourth and fifth year were, respectively, 96%, 92%, 88%, 82% and 78%. Bleeding problems were the most common cause for removal. The cumulative five-year net pregnancy rate for Norplant was 1.8 per 100 women. The Norplant contraceptive system is thus seen to combine the highest acceptability as measured by its continuation rate with the highest long-term effectiveness among the available temporary contraceptive methods.

PIP: Norplant contraceptive implants were inserted into 437 Indonesian women aged 18-40 years of diverse educational backgrounds from May 1 until Aug. 31, 1981. The continuation rates for use of the implants at the 1st, 2nd, 3rd, 4th, and 5th year were 96%, 92%, 88%, 82%, and 78%, respectively. Bleeding problems were the most common cause for removal of the implant. The cumulative 5-year net pregnancy rate for Norplant was 1.8 pregnancies/100 women. The Norplant contraceptive system appears to combine the highest acceptability as measured by its continuation rate with the highest long-term effectiveness among the available temporary contraceptive methods.

Pregnancy after removal of Norplant implants contraceptive.

Many concerns have been expressed regarding the introduction of a new contraceptive method into family planning programmes. One of the concerns is the return of fertility after discontinuing the method. To evaluate the subsequent fertility status of the Indonesian women after removal of Norplant, a prospective longitudinal study was undertaken in Klinik Radeb Saleh, Jakarta. Fifty-one women whose Norplant were removed because of their wish to become pregnant were followed-up for a period of two years or until pregnancy occurred, whichever was earlier. Two groups of women who had Lippes C IUD removed or discontinued the use of DMPA for planning pregnancy served as control and were followed-up for equal length of time. The cumulative conception rate for ex-Norplant users, ex-IUD users and ex-DMPA users at one year was 76.5, 74.7 and 70.2 per 100 women, respectively. There was no significant difference between the groups (p greater than 0.05). The present study, along with other studies, indicate that the prolonged use of Norplant do not impair the return of fertility.

PIP: Many concerns have been expressed regarding the introduction of a new contraceptive method into family planning programs. One of the concerns is the return of fertility after discontinuing the method. To evaluate the subsequent fertility status of the Indonesian women after removal of Norplant, a prospective longitudinal study was undertaken in Klinik Radeb Saleh, Jakarta. 51 women whose Norplant were removed because of their wish to become pregnant were followed-up for a period of 2 years or until pregnancy occurred, whichever was earlier. 2 groups of women who had Lippes C IUD removed or discontinued the use of DMPA for planning pregnancy served as control and were followed-up for equal length of time. The cumulative conception rate for ex-Norplant users, ex-IUD users, and ex-DMPA users at 1 year was 76.5, 74.7, and 70.2 per 100 women, respectively. There was no significant difference between the groups (p 0.05). The present study, along with other studies, indicate that the prolonged use of Norplant does not impair the return of fertility.

Multicenter clinical trial on the efficacy and acceptability of a single contraceptive implant of nomegestrol acetate, Uniplant.

Uniplant, a single Silastic implant containing nomegestrol acetate, provides contraceptive efficacy for one year. Uniplant use for one year was studied in 1,803 healthy women of reproductive age, enrolled from 10 centers in 9 countries, after informed consent. Implants were placed subdermally either in the upper arm or in the gluteal region. Two-hundred-seventy-six subjects discontinued prior to completing one year of study. Cumulative discontinuation rate at 12 months was 15.72%. Medical reasons for discontinuation were principally menstrual-related. Fifteen pregnancies occurred during the one year study period, resulting in a 12-month net cumulative pregnancy rate of 0.94%. Approximately 56% of subjects using Uniplant had bleeding patterns similar to normal menstruation. Results from this study confirm that Uniplant is an efficient, well tolerated, 12-month contraceptive implant, with the advantage of easier insertion and removal of the single implant compared to other multiple implant methods.

Norplant consensus statement and background review.

This review has highlighted the attributes of a very important new method of contraception. The signatories to this document agree that, with the provision of appropriate information and instruction for the user, Norplant is a good contraceptive choice to be made available worldwide in family planning programs that have the resources for appropriate training and counseling. The signatories to this document are acting in their own personal capacity and not as representatives of any particular organization.

PIP: The Norplant contraceptive implant has been registered in 60 countries and used by over 6 million women worldwide. Clinical studies have repeatedly confirmed this method's long-term efficacy and safety when used appropriately. Preliminary findings of the Post-Marketing Surveillance study of Norplant, a 5-year prospective study conducted in 32 family planning clinics in 8 developing countries in 1987-97, indicate an intrauterine pregnancy rate of 0.23/100 woman-years, an ectopic pregnancy rate of 0.03/100 woman-years, and a 67.3% continuation rate at 5 years. No significant excess of malignant neoplastic or cardiovascular disease has been observed. The major side effect is an irregular pattern of uterine bleeding, associated with about 25% of the discontinuations after 5 years of use. The quality of the family planning service is a major determinant of successful Norplant use and the degree of user satisfaction. Informed choice, the quality of follow-up care, easy access to removal services, and provider skills and attitudes are also critical. The signatories to this Consensus Statement (acting as individuals rather than representatives of their organizations) agree that, with the provision of appropriate information to users, Norplant is a good contraceptive choice that should be made available globally in all family planning programs with resources for appropriate training and counseling.

Peritoneal factors in infertile women in Jakarta, Indonesia.

In a study of internal genital infection and endometriosis, gynecologic examinations discovered only 46 patients (14.9%) with these abnormalities out of 308, but laparoscopic examinations of the same patients detected far more patients with these abnormalities (208, or 67.5%). Thus, laparoscopic examinations can prove useful in improving the clinical diagnosis of infertility in women.

The effect of Norplant on some hemostatic parameters in Indonesian women.

Many reports have indicated that oral contraceptives can increase the incidence of thromboembolic disorders. Norplant, an implant contraceptive containing levonorgestrel, has been developed recently. The aim of this study is to observe the effect of Norplant on some hemostatic parameters. The subjects in this study were divided into 5 groups. Group 1 (control) consisted of 25 female blood donors. Group 2 (N = 25), group 3 (n = 25), group 4 (n = 17) and group 5 (N = 20) consisted of subjects who had been using Norplant for 2, 3, 4, and 5 years, respectively. Prothrombin time, activated partial thromboplastin time, fibrinogen level, assay of F VII and X, antithrombin III activity, plasminogen activity, alpha 2-plasmin inhibitor activity and platelet aggregation test were done in all subjects. Our results showed that there was a significant difference (p < 0.05) on platelet aggregation induced by 10 microM of ADP between the control group and Norplant users for more than 2 years, while the other parameters did not differ significantly. It is concluded that 5 years users of Norplant did not alter blood coagulability, but increased platelet response to 10 microM of ADP.

Endometrial biopsy collection from women receiving Norplant.

A series of 191 endometrial biopsy procedures were performed on Indonesian women who had received between 3 and 12 months exposure to Norplant. In all, 87 biopsy procedures were attempted with a microhysteroscope using biopsy forceps, and 104 procedures were attempted with either Pipelle or Karman suction curettes. Regardless of the biopsy method, diagnosable endometrium was obtained in only approximately 50% of procedures. Myometrium was often found in microhysteroscope but not in suction biopsies. An analysis of a number of clinical characteristics showed that women from whom diagnosable endometrial tissue was obtained had higher mean peripheral oestrogen concentrations in the 2 weeks prior to biopsy (439 +/- 35 versus 289 +/- 33 pmol/l; P = 0.0018) and significantly more days when endometrial bleeding occurred in the 90 days prior to biopsy (26.5 +/- 2.1 versus 16.2 +/- 1.8; P = 0.0003). These results suggest that after 3-12 months exposure to Norplant approximately 50% of women have an endometrium too thin to sample, and that this group is characterized by lower peripheral oestrogen concentrations and reduced menstrual bleeding.

PIP: Research on the causes of progestogen-induced breakthrough bleeding in Norplant users depends on the availability of endometrial biopsy samples. In this study, 3 biopsy techniques were utilized in 191 Indonesian women with 3-12 months of exposure to Norplant: microhysteroscopy with biopsy forceps (n = 87), Pipelle suction curette (n = 52), and Karman cannula (n = 52). Diagnosable endometrium were obtained in 51%, 42%, and 58% of these procedures, respectively. Use of the microhysteroscope often resulted in the collection of full thickness endometrium, including a small amount of myometrial tissue, but the endometrium was always very thin or absent. In contrast, both the suction curette techniques collected endometrial tissue only. Women from whom successful endometrial biopsies were obtained tended to have significantly more days of endometrial bleeding in the 90 days preceding biopsy (26.5 +or- 2.1 versus 16.2 +or- 1.8) and higher mean peripheral estrogen concentrations in the 2 weeks preceding biopsy (439 +or- 35 versus 289 +or- 33 pmol/l). The fact that the group from which successful biopsies are obtained may not be representative of all Norplant users should be considered in the analysis of clinical research.

Immunohistochemical detection of cathepsin D in endometrium from long-term subdermal levonorgestrel users and during the normal menstrual cycle.

A previous report has shown that progesterone up-regulates cathepsin D expression in human endometrial cell culture. In women using the levonorgestrel-releasing Implant Norplant, the plasma levonorgestrel and immunoreactive endometrial progesterone receptor concentrations are elevated. However, the functional status of these receptors is not known. This study used endometrial cathepsin D expression both as an indirect marker for the functional status of endometrial progesterone receptors, and to identify the cell types that express cathepsin D. The results show that cathepsin D is primarily found in glandular epithelia and luminal epithelia in control and Norplant endometria. There is no significant difference in cathepsin D expression between the control and Norplant endometria, between the various stages of the menstrual cycle, or between Norplant users with varying degrees of breakthrough bleeding. Cathepsin D is also detected in cells scattered in the stroma in both control and Norplant endometria. The majority of these cells are macrophages. These data indicate that there is no evidence for progesterone regulation of cathepsin D in the human endometrium. Cathepsin D thus cannot be used as a marker for the functional status of progesterone receptors found in the Norplant-exposed endometrium.

Perivascular smooth muscle alpha-actin is reduced in the endometrium of women with progestin-only contraceptive breakthrough bleeding.

It has been shown that the endometrium of women using progestin-only contraceptives has increased vascular fragility, although the structural basis for this weakness is unknown, as is its role in breakthrough bleeding (BTB). Perivascular cells such as pericytes and vascular smooth muscle cells surround capillaries during the maturation process following angiogenesis, and act to strengthen and stabilize the vessels. The aim of the present study was to quantify endometrial perivascular smooth muscle alpha-actin (alphaSMA) expression in women using Norplant with and without BTB problems, and compare it to controls. Using immunohistochemical techniques, vessels were classified as level 0, 1 or 2 depending on whether perivascular alphaSMA was absent, discontinuous or continuous. In 15 controls the subepithelial plexus had significantly more level 0 vessels than either the functionalis or basalis (61 +/- 4 versus 31 +/- 6 and 37 +/- 4%, P = 0.0006 and P = 0.0007 respectively). In contrast the functionalis and basalis had significantly more level 2 vessels than the subepithelial plexus (20 +/- 3 and 23 +/- 2 compared to 4 +/- 1%, P = 0.0005 and P = 0.000 respectively). The major finding of the study was that in Norplant users, where the relatively atrophic endometrium cannot be divided into different regions, women with BTB problems (n = 20) had significantly more level 0 vessels than those with reduced bleeding (n = 17) (60 +/- 4 versus 46 +/- 4%, P = 0.0302). Norplant users with BTB problems also had a non-significant reduction in level 2 vessels compared to women without bleeding problems (4 +/- 2 versus 11 +/- 4%, P = 0.0667). These results demonstrate that perivascular alphaSMA is reduced around the endometrial vessels of Norplant users with BTB compared to those with no bleeding problems, and strongly support the concept that reduced vascular structural integrity plays a key role in endometrial BTB.