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BACKGROUND: Hyperproliferation of smooth muscle cells (SMCs) plays a key role in allograft arteriosclerosis. This prompted us to investigate the effect of the novel immune modulator and synthetic sphingolipid FTY720 on apoptosis of SMCs. METHODS: Rabbit SMC cultures were treated with FTY720 and apoptosis and necrosis were detected by fluorescence microscopy. RESULTS: We investigated dose- and time-dependent effects of FTY720 and found that clinically relevant low doses of FTY720 (<1 micromol/L) did not induce apoptosis, whereas 10 micromol/L FTY720 induced apoptosis after 48 hours incubation. CONCLUSION: At doses of FTY720 used in clinics for treatment of renal allografts and multiple sclerosis. FTY720 did not induce SMC apoptosis.

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Although fertility declines with advancing age as the woman approaches the menopause, some risk of pregnancy persists, and effective contraception needs to be offered to avoid an unintended pregnancy. An older woman may have menstrual dysfunction or climacteric symptoms and these factors would need consideration when making the choice of contraception. Low-estrogen dose combined oral contraceptives may be prescribed to healthy non-smoking women up to about 50 years of age. The progestogen-only pill may be an appropriate option in an older woman with declining fertility. The copper intrauterine device is an optimal method for parous women free of pre-existing menstrual problems. The levonorgestrel-releasing intrauterine system is considered the contraceptive method of choice for perimenopausal women with menstrual dysfunction. The woman should be provided with individualized advice so that she has a choice between the newer, effective, largely safe, reversible methods and sterilization.

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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.

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BACKGROUND: In the 1970s a new approach to the delivery of hormonal contraception was researched and developed. It was suggested that the addition of a progestogen to a non-medicated contraceptive device improved its contraceptive action. An advantage of these hormonally impregnated intrauterine systems (IUS) is that they are relatively maintenance free, with users having to consciously discontinue using them to become pregnant rather than taking a proactive daily decision to avoid conception. OBJECTIVES: To assess the contraceptive efficacy, tolerability and acceptability of hormonally impregnated intrauterine systems (IUSs) in comparison to other reversible contraceptive methods. SEARCH STRATEGY: Literature was identified through database searches, reference lists and individuals/organisations working in the field. Searches covered the period from 1972 to November 2003. SELECTION CRITERIA: All randomised controlled trials comparing IUSs with other forms of reversible contraceptives and reporting on pre-determined outcomes in women of reproductive years. The primary outcomes were pregnancy due to method/user failure and continuation rate. DATA COLLECTION AND ANALYSIS: The quality assessment of studies and data extraction were completed independently by two blinded reviewers. A quality checklist was designed to identify general methodological and contraceptive specific factors which could bias results. Events per women months and single decrement life table rates were extracted where possible for pregnancy, continuation, adverse events and reasons for discontinuation. Events per total number of women at follow up were collected for hormonal side effects and menstrual disturbance. When appropriate, data were pooled at the same points of follow up to calculate rate ratios in order to determine the relative effectiveness of one method compared to another. For the single decrement life table rates, the rate differences were pooled to determine the absolute difference in effectiveness of one method compared to another. Interventions were only combined if the contraceptive methods were similar. Non-hormonal IUDs were divided into three categories for the purpose of comparison with IUSs: IUDs >250mm2 (i.e. CuT 380A IUD and CuT 380 Ag IUD), IUDs <=250mm2 (i.e. Nova-T, Multiload, CuT 200 and CuT 220 IUDs) and non-medicated IUDs. MAIN RESULTS: Twenty-one RCTs comparing hormonally impregnated IUSs to a reversible contraceptive method met the inclusion criteria and it was possible to include eight of these in the meta-analyses, four comparing LNG-20 IUSs with non-hormonal IUDs, one comparing the LNG-20 IUS with Norplant-2 and three comparing Progestasert with non-hormonal IUDs. No significant difference was observed between the pregnancy rates for the LNG-20 users and those for the IUD >250mm2 users. However, women using the LNG-20 IUS were significantly less likely to become pregnant than those using the IUD <=250mm2. Women using the LNG-20 IUS were more likely to experience amenorrhoea and device expulsion than women using IUDs >250mm2. LNG-20 users were significantly more likely than all the IUD users to discontinue because of hormonal side effects and menstrual disturbance, which on further breakdown of the data was due to amenorrhoea. When the LNG-20 IUS was compared to Norplant-2, the LNG-20 users were significantly more likely to experience amenorrhoea and oligomenorrhoea, but significantly less likely to experience prolonged bleeding and spotting. No other significant differences were observed. Progestasert users were significantly less likely to become pregnant and less likely to continue on the method than non-medicated IUD users after one year, but no significant difference was noted for these two outcomes when Progestasert users were compared to IUD<=250mm2 users. The only other significant differences found in the meta-analyses were that Progestasert users were less likely to expel the device and more likely to discontinue the method because of menstrual bleeding and pain than users of IUDs <=250mm2. REVIEWERS' CONCLUSIONl the device and more likely to discontinue the method because of menstrual bleeding and pain than users of IUDs <=250mm2. REVIEWERS' CONCLUSIONS: Current evidence suggests LNG-20 IUS users are no more or less likely to have unwanted pregnancies than IUD >250mm2 and Norplant-2 users. The LNG-20 IUS was more effective in preventing either intrauterine or extrauterine pregnancies than IUDs <=250mm2. The contraceptive effectiveness of Progestasert was significantly better than non-medicated IUDs, but no difference was observed when compared to IUDs<=250mm2. Continuation of LNG-20 IUS use was similar to continuation of the non-hormonal IUDs and Norplant-2. Amenorrhoea was the main reason for the discontinuation for the LNG-20 IUS and women should be informed of this prior to starting this method.

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The first 200 women to be fitted with GyneFix at the Margaret Pyke Centre, a National Health Service contraception clinic situated in central London, have been followed up at 1 year after insertion. Removals, expulsions and accidental pregnancies in that first year are recorded. Of the cohort, 80% had a known outcome at 12 months. There was one perforation with the inserter tube, leaving 199 women fitted with GyneFix who contributed 2033 woman-months of follow-up time. We recorded 22 early removals, of which 16 were for heavy or irregular bleeding and/or pain, three were because the women wished to conceive and three for other reasons. In addition there were 16 expulsions at intervals ranging from 1 day to 12 months after insertion. Four of the expulsions were unnoticed by the subjects (they were revealed by amenorrhea of pregnancy in two subjects and lost threads in the other two). There were no pregnancies with the GyneFix in situ. The expulsion rate of 8.4% (confidence interval (CI) 5.2-13.4%) and removal rate for bleeding and/or pain of 9.0% (CI 5.6-14.3%) at 12 months recorded in this cohort fall within acceptable ranges for framed intrauterine devices in a population with a large percentage of nulliparous women. However, they are perhaps not as good as had been anticipated for this revolutionary new intrauterine implant. Possible reasons for this are explored.

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OBJECTIVE: To assess the short-term acceptability and functionality of the eZ.on condom compared with currently marketed latex (Gossamer) and polyurethane (Avanti) condoms. Method Healthy, sexually active volunteers aged 18-50 years, self-selected from among the UK population, were enrolled in a randomized cross-over trial. Participants were required to test six of each of three condom variants. Data were collected on structured questionnaires by means of postal and telephone contacts. Main outcome measures were breakage and slippage rates, and short-term user acceptability based on participants' ratings documented in end-of-study questionnaires. RESULTS: Forty-three couples entered the study, of whom 37 tested the condoms on 512 occasions. There was no statistically significant difference in the clinical breakage rate between eZ.on (3.7%) and the comparator condoms (3.5% for Gossamer and 2.9% for Avanti). Complete slippage rates were similar for eZ.on (2.4%) and Avanti (2.9%). Gossamer had the lowest slippage rate (1.2%), but this difference was not statistically significant. User acceptability was similar for the three condom types; however, there was a trend for more participants to express dissatisfaction with eZ.on, including difficulties with putting on the condom. CONCLUSIONS: No firm conclusions can be drawn from this pilot study, but our observations suggest that eZ.on may be an acceptable option for some couples unwilling or unable to use a latex condom.

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OBJECTIVE: To investigate depot medroxyprogesterone (DMPA)-associated bone loss in a general practice setting. DESIGN: Forty-eight patients from a single practice who had used DMPA for contraception for more than 2 years. All patients had a serum oestradiol and if the serum level was <52 pmol/l or >52 pmol/l with menopausal symptoms, bone mineral densitometry (BMD) measurements were made at the lumbar spine (LS) and femoral neck (FN) using dual-energy x-ray absorptiometry (DEXA). Thirty-two patients had bone densitometry, of whom 27 had a serum oestradiol <52 pmol/l and five >52 pmol/l associated with menopausal symptoms. Of the remaining 16 patients, nine patients had a serum oestradiol <52 pmol/l but did not have a BMD as they moved away (five women) or switched to another contraceptive (four women). RESULTS: BMD results showed a significantly reduced bone mass at both sites with mean Z score LS -0.84 (95% CI -1.17 to -0.52) and FN -0.32 (95% CI -0.62 to -0.02). Eighteen women (56% of 32 women) had either osteopenia (15 cases) (T score < -1.0) or osteoporosis (three cases) (T score < -2.5) at the LS. There were trends to an association of a family history of height loss or tobacco smoking (current or past) for LS and FN Z scores that did not quite achieve significance. There was also a trend to lower body weight in those with a possible family history of osteoporosis or who were smokers and an inverse correlation of weight with BMD at the FN (p < 0.05) and a non-significant inverse correlation at the LS. CONCLUSION: The present results demonstrate that a low bone mass should be considered in patients with prolonged DMPA usage especially if they have risk factors for osteoporosis.

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This study aimed to identify specific haemostatic changes that might account for previous observations of higher venous thromboembolic risk among users of combined oral contraceptives (COCs) containing desogestrel (DSG) than levonorgestrel (LNG). Sixty-three current users of monophasic 30 microg oestrogen COCs containing either LNG or DSG omitted one pill-free interval (PFI), switching immediately either to the opposite formulation for one cycle or continuing with the same pill. Venesection followed the initial PFI after one cycle (21 tablets) and two cycles (42 tablets) of continuous pill taking, and after the following PFI. Protein S was lower in users of DSG than LNG formulations after the first PFI (mean +/- SD, 0.67 +/- 0.09 vs 0.76 +/- 0.10, P < 0.001) and after one cycle (0.61 +/- 0.09 vs 0.76 +/- 0.09, P < 0.0001). Protein S decreased when switching from LNG to DSG pills (0.77 +/- 0.07-0.65 +/- 0.06, P < 0.0001), mirrored by an increase at switching from DSG to LNG formulations (0.61 +/- 0.08-0.73 +/- 0.10, P < 0.005). Mean protein S levels remained within the normal range. Three different markers of thrombin generation remained unaltered. Potential explanations for COC-related thrombotic events are 'acquired resistance to activated protein C' or inhibition of fibrinolysis. A potential role has been described for protein S deficiency in both. A further triggering factor is a probable prerequisite for actual thrombosis, but pill-takers whose levels of protein S were in the lowest percentiles may be at greatest risk.

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OBJECTIVES: To assess the contraceptive efficacy, tolerability and acceptability of hormonally impregnated intrauterine systems (IUSs) in comparison to other reversible contraceptive methods. SEARCH STRATEGY: Literature was identified through database searches, reference lists and individuals/organisations working in the field. SELECTION CRITERIA: All randomised controlled trials comparing IUSs with other forms of reversible contraceptives and reporting on pre-determined outcomes in women of reproductive years. The primary outcomes were pregnancy due to method/user failure and continuation rate. DATA COLLECTION AND ANALYSIS: The quality assessment of studies and data extraction were completed independently by two blinded reviewers. A quality checklist was designed to identify general methodological and contraceptive specific factors which could bias results. Events per women months and single decrement life table rates were extracted where possible for pregnancy, continuation, adverse events and reasons for discontinuation. Events per total number of women at follow up were collected for hormonal side effects and menstrual disturbance. When appropriate, data were pooled at the same points of follow up to calculate rate ratios in order to determine the relative effectiveness of one method compared to another. For the single decrement life table rates, the rate differences were pooled to determine the absolute difference in effectiveness of one method compared to another. Interventions were only combined if the contraceptive methods were similar. Non-hormonal IUDs were divided into three categories for the purpose of comparison with IUSs: IUDs >250mm2 (i.e. CuT 380A IUD and CuT 380 Ag IUD), IUDs <=250mm2 (i.e. Nova-T, Multiload, CuT 200 and CuT 220 IUDs) and non-medicated IUDs. MAIN RESULTS: Nineteen RCTs comparing hormonally impregnated IUSs to a reversible contraceptive method met the inclusion criteria and it was possible to include eight of these in the meta-analyses, four comparing LNG-20 IUSs with non-hormonal IUDs, one comparing the LNG-20 IUS with Norplant-2 and three comparing Progestasert with non-hormonal IUDs. No significant difference was observed between the pregnancy rates for the LNG-20 users and those for the IUD >250mm2 users. However, women using the LNG-20 IUS were significantly less likely to become pregnant than those using the IUD <=250mm2. Women using the LNG-20 IUS were more likely to experience amenorrhoea and device expulsion than women using IUDs >250mm2. LNG-20 users were significantly more likely than all the IUD users to discontinue because of hormonal side effects and menstrual disturbance, which on further breakdown of the data was due to amenorrhoea. When the LNG-20 IUS was compared to Norplant-2, the LNG-20 users were significantly more likely to experience amenorrhoea and oligomenorrhoea, but significantly less likely to experience prolonged bleeding and spotting. No other significant differences were observed. Progestasert users were significantly less likely to become pregnant and less likely to continue on the method than non-medicated IUD users after one year, but no significant differences was noted for these two outcomes when Progestasert users were compared to IUD<=250mm2 users. The only other significant differences found in the meta-analyses were that Progestasert users were less likely to expel the device and more likely to discontinue the method because of menstrual bleeding and pain than users of IUDs <=250mm2. REVIEWER'S CONCLUSIONS: Current evidence suggests LNG-20 IUS users are no more or less likely to have unwanted pregnancies than IUD >250mm2 and Norplant-2 users. The LNG-20 IUS was more effective in preventing either intrauterine or extrauterine pregnancies than IUDs <=250mm2. The contraceptive effectiveness of Progestasert was significantly better than non-medicated IUDs, but no difference was observed when compared to IUDs<=250mm2. Continuation of LNG-20 IUS use was similar to continuation of the non-hormonal IUDs and Norplant-2. Amenorrhoea was the main reason for the discontinuation for the LNG-20 IUS and women should be informed of this prior to starting this method.

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Rising each year by around 85 million, we have started this millennium with over 6,000 million, mostly utterly destitute, human beings on a finite planet. We will never meet human needs without stabilizing human numbers. In the sexual arena, all human beings (but especially the males of the species) are very bad at using their brains and their genitalia at the same time, i.e. putting the knowledge in their head about risks of conception or of sexually transmitted infections into appropriate preventive action when sexually aroused! Therefore, a very useful criterion for choice of methods all through the various stages of reproductive life is 'forgettability'. This is a great 'plus' point for the intrauterine route, especially the levonorgestrel intrauterine system (LNG-IUS). Its main contraceptive effects are local, by endometrial suppression and changes to the cervical mucus and uterotubal fluid, which impair sperm migration. The blood levels of levonorgestrel are about one-quarter of the peak levels in users of the progestin-only pill, and so gestagenic symptoms are uncommon and ovarian function is little altered. Most women continue to ovulate and, in the remainder, sufficient estrogen for health is produced from the ovary even if they become amenorrheic, as many do; this is primarily a local end-organ effect and should be seen as a benefit. Postmenopausal estradiol levels have not been detected, even in those who have no uterine bleeding. Although usable by selected nulliparae, the LNG-IUS is a particularly good choice for the parous woman, for whom I maintain it represents the future already here, which is not recognized by many providers. It has unsurpassed efficacy; 99.5% of women have not conceived after 5 years of use. Return of fertility is rapid and appears to be complete. Combining the best features of hormonal and intrauterine contraception without most ofthe problems of either, it fundamentally 'rewrites the textbooks' about intrauterine devices. Its gynecological benefits are impressive: the LNG-IUS user can expect a dramatic reduction in amount and, after the first few months, in duration of blood loss. Dysmenorrhea is also greatly benefited, in most cases. In summary, the LNG-IUS fulfils many of the criteria for an 'ideal' contraceptive. Adverse side-effects are few and, in general, they are not in the category 'hazardous'. Regarding the inconvenience of the first weeks of light post-insertion bleeding and the early-phase low incidence ofsteroidal side-effects, forewarned is forearmed!

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OBJECTIVE: To investigate the effects of stopping smoking on cervical Langerhans' cells and lymphocytes. DESIGN: Prospective intervention study. SETTING: A large family planning clinic in central London. POPULATION: Women volunteers prepared to attempt to give up smoking for six months. Their most recent cervical smear showed no abnormality greater than mild dyskaryosis. METHODS: The women were seen at three-month intervals for six months. Reduction in smoking was assessed by self-reporting and validated by salivary cotinine concentrations. Colposcopy and a biopsy of a normal area were performed at the first and last visits. Any area of abnormality was also biopsied at the final visit. Langerhans' cells and lymphocytes were counted. MAIN OUTCOME MEASURES: Proportional changes in counts of Langerhans' cells and lymphocytes with reduction in smoking. RESULTS: Reduction in smoking by 20 to 40 cigarettes per day was significantly associated with a reduction of between 6% and 16% in counts of Langerhans cells, CD8 and total lymphocytes. Heavy smoking was significantly associated (P = 0.02) with an increased chance of persistent human papillomavirus infection. The presence of candida was associated with significantly higher counts of between 41% and 47% in total lymphocytes and CD8 lymphocytes. In contrast, the presence of anaerobic vaginosis was associated with significantly lower counts of between 16% and 30% in Langerhans cells, CD4 and CD8 lymphocytes. CONCLUSIONS: This large intervention study has demonstrated a clear relationship between reduction in smoking and changes in cervical immune cell counts. Future studies need to take into account cytokine interactions, which recent studies suggest may be significant in the immune response to both human papillomavirus and cervical intraepithelial neoplasia and the ever-increasing complexity of the cell-mediated immune system of the cervix.

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Rising each year by around 85 million, we have started this millennium with over 6,000 million, mostly utterly destitute, human beings on a finite planet. We will never meet human needs without stabilizing human numbers. In the sexual arena, all human beings (but especially the males of the species) are very bad at using their brains and their genitalia at the same time, i.e. putting the knowledge in their head about risks of conception or of sexually transmitted infections into appropriate preventive action when sexually aroused! Therefore, a very useful criterion for choice of methods all through the various stages of reproductive life is 'forgettability'. This is a great 'plus' point for the intrauterine route, especially the levonorgestrel intrauterine system (LNG-IUS). Its main contraceptive effects are local, by endometrial suppression and changes to the cervical mucus and uterotubal fluid, which impair sperm migration. The blood levels of levonorgestrel are about one-quarter of the peak levels in users of the progestin-only pill, and so gestagenic symptoms are uncommon and ovarian function is little altered. Most women continue to ovulate and, in the remainder, sufficient estrogen for health is produced from the ovary even if they become amenorrheic, as many do; this is primarily a local end-organ effect and should be seen as a benefit. Postmenopausal estradiol levels have not been detected, even in those who have no uterine bleeding. Although usable by selected nulliparae, the LNG-IUS is a particularly good choice for the parous woman, for whom I maintain it represents the future already here, which is not recognized by many providers. It has unsurpassed efficacy; 99.5% of women have not conceived after 5 years of use. Return of fertility is rapid and appears to be complete. Combining the best features of hormonal and intrauterine contraception without most ofthe problems of either, it fundamentally 'rewrites the textbooks' about intrauterine devices. Its gynecological benefits are impressive: the LNG-IUS user can expect a dramatic reduction in amount and, after the first few months, in duration of blood loss. Dysmenorrhea is also greatly benefited, in most cases. In summary, the LNG-IUS fulfils many of the criteria for an 'ideal' contraceptive. Adverse side-effects are few and, in general, they are not in the category 'hazardous'. Regarding the inconvenience of the first weeks of light post-insertion bleeding and the early-phase low incidence ofsteroidal side-effects, forewarned is forearmed!

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The supremacy of combined oral contraceptives (OCs) is being challenged. For too long combined OCs have been seen as synonymous with contraception, helping to maintain ignorance of alternative methods. Further, the efficacy of these OCs and condoms is often compromised by incorrect or inconsistent use. We particularly welcome developments in male systemic methods, that allow men to share not only in conception but also in contraception, and methods that are completely forgettable once instituted, especially if usable by adolescents.

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OBJECTIVE: To assess the relative contraceptive effectiveness, tolerability and acceptability of the levonorgestrel-releasing (20 microg per day) intrauterine system (LNG-20) compared with reversible contraceptive methods in women of reproductive age. DESIGN: A systematic review and meta-analysis of randomised controlled trials. IDENTIFICATION: Studies were identified through seven databases, and by contacting investigators and organisations working in the contraceptive field. MAIN OUTCOME MEASURES: Unplanned pregnancy and continuation of contraceptive method. RESULTS: Five of the seven randomised controlled trials which met the inclusion criteria were included in the meta-analyses; four were comparisons of the LNG-20 intrauterine system with nonhormonal intrauterine devices. LNG-20 intrauterine systems were compared with intrauterine devices divided into two categories, those > 250 mm3 (Copper T 380 Ag and Copper T 380A intrauterine devices) and those < or = 250 mm3 (Nova-T, Copper T 220C and Copper 200 intrauterine devices). Pregnancy rates for the LNG-20 intrauterine system users were significantly less likely to become pregnant compared with users of intrauterine devices < or = 250 mm3, and significantly less likely to have an ectopic pregnancy. LNG-20 intrauterine system users were more likely to experience amenorrhoea and device expulsion than women using intrauterine devices > 250 mm3. LNG-20 intrauterine system users were significantly more likely than all the intrauterine device users to discontinue because of hormonal side effects and amenorrhoea. When the LNG-20 intrauterine system was compared with Norplant-2, the LNG-20 users were significantly more likely to experience oligo-amenorrhoea, but significantly less likely to experience prolonged bleeding and spotting. CONCLUSIONS: The effectiveness of the LNG-20 intrauterine system was similar to or better than other contraceptive methods with which it was compared. Amenorrhoea was the main reason for the discontinuation of the LNG-20 intrauterine system, usually unnecessarily, since this end-organ suppression of bleeding is benign, associated with normal oestrogen levels. Women choosing this method should be informed of potential amenorrhoea when having pre-contraceptive counselling and that absent bleeding may be viewed as a positive outcome.

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