Effect of FTY720 on apoptosis of smooth muscle cells.

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.

Group B streptococci in women fitted with intrauterine devices.

A survey was made of group B streptococcal carriage at various sites in 100 women attending a clinic for the insertion of an intrauterine contraceptive device (IUD). Twenty-three women carried streptococci at one or more sites at the preinsertion visit, the vaginal carriage rate being 16%. Six months after insertion changes in carrier status were noted and there was evidence of a change of strain in four patients. Twenty-nine women were carriers at one or more sites at some stage of the study. There was no evidence that symptoms attributable to infection in patients fitted with an IUD were caused by group B streptococci.

Vasitis nodosa and associated clinical findings.

To establish the prevalence of vasitis nodosa in patients who had undergone vasectomy segments of vas deferens resected from 40 patients at the time of vasectomy reversal were examined histologically and immunohistochemically. The findings were correlated with clinical history and postoperative outcome. Controls comprised segments of normal vas deferens excised at vasectomy. Twenty of the 40 vasovasostomy specimens showed vasitis nodosa; in 13 this was associated with sperm granulomas and in two with spermatocoeles. The vasitis nodosa was characterised by multiple small ductules extending from the central lumen of the vas into the muscle layers and adventitia. In 14 cases there was mucinous metaplasia of the epithelium lining the ductules. The number of nerve fibres in the submucosa and muscle layers was reduced after vasectomy. In patients with vasitis, however, hyperplasia of nerve fibres in the adventitia (16 of 20 cases) and formation of neuromas were seen. Nerve fibre hyperplasia was seen in only one, and sperm granulomas and spermatocoeles in none of the 20 specimens without vasitis nodosa. The development of vasitis nodosa was independent of the patients' age or the interval between vasectomy and reversal. The restoration of fertility did not seem to be affected by previous vasitis nodosa.

Paired cervical smears: a method of reducing the false-negative rate in population screening.

Cervical smears taken by the wooden Ayre spatula (widely used in the United Kingdom) and by a plastic spatula (Armovical) were compared for their ability to detect dysplastic cervical epithelium and endocervical cells. At the same time, the value of taking duplicate smears was assessed. Paired cervical smears were obtained at a single attendance from 21,352 women, using the 2 types of spatulas in 4 different sequences. Although individually the Armovical proved superior to the Ayre spatula for the collection of endocervical epithelial material, this advantage was not complemented by any marked improvement in its detection of cervical dysplasia. Paired smear sampling, however, was clearly more rewarding in this respect and also allowed the introduction of laboratory quality control, as each preparation of any given pair was examined by a different screener. The false-negative rate was 18.5%: it comprised 11.1% sampling error and 7.4% screening error. It is concluded that paired smear sampling in population screening would significantly reduce the false-negative rate.

A risk-benefit assessment of the levonorgestrel-releasing intrauterine system.

The levonorgestrel-releasing intrauterine system (LNG-IUS), has been developed by Leiras Pharmaceuticals, Turku, Finland. It is a new systemic hormonal contraceptive that releases levonorgestrel 20 micrograms every 24 hours. The device provides fertility control comparable with that of female sterilisation, complete reversibility and convenience, and has an excellent tolerability record. The low dosage of levonorgestrel released by its unique delivery system ensures minimal hormone-related systemic adverse effects, which tend to be in the category of 'nuisance' rather than hazardous, and gradually diminish after the first few months of use. In some respects, the contraceptive characteristics of the LNG-IUS have over-shadowed a substantial range of noncontraceptive beneficial effects that are rarely seen with inert or copper-releasing intrauterine contraceptive devices (IUDs), and have important and positive gynaecological and public health implications. This applies particularly to the profound reduction in duration and quantity of menstrual bleeding, and alleviation of dysmenorrhoea, which are associated with the use of the device. Recent studies have shown that the LNG-IUS is effective in preventing endometrial proliferation associated with oral or transdermal estradiol therapy, and in inducing regression of endometrial hyperplasia. Further research is required to determine whether it has a role in regulating the growth of uterine fibroids, and preventing pelvic inflammatory disease. The unique unwanted noncontraceptive effects of the system, including possible development of functional ovarian cysts, and the relationship between menstrual bleeding pattern and ovarian function, also require better understanding, in order to offer appropriate patient counselling and maximise acceptability and continuation of use of the method.

PIP: The levonorgestrel-releasing intrauterine system (LNG-IUS) provides fertility control comparable to female sterilization, convenience, and complete reversibility. This method appears to combine the benefits of oral contraception and the IUD, while avoiding most of their side effects. The low level of LNG released (20 mcg every 24 hours) minimizes the systemic adverse effects associated with hormonal contraception. Unlike inert or copper IUDs, the LNG-IUS is associated with a profound reduction in the duration and quantity of menstrual bleeding and alleviates dysmenorrhea. Moreover, there is evidence that the LNG-IUS prevents the endometrial proliferation associated with estradiol therapy and induces regression of endometrial hyperplasia; its potential for regulating the growth of uterine fibroids and preventing pelvic inflammatory disease remains undetermined. Although large multicenter studies have not detected differences in cervical cytology or breast cancer incidence between copper IUD and LNG-IUS users, long-term epidemiological studies are needed to confirm this finding. Fundal positioning of the LNG-IUS is essential to ensure uniform exposure of the endometrium to the progestogen, prevent expulsion, and maximize efficacy. A promising future use for the LNG-IUS is in protecting the endometrium during postmenopausal hormone replacement therapy. Overall, the research suggests that the LNG-IUS comes close to meeting many of the requirements of an ideal contraceptive.

Functional characterization of alpha1-adrenoceptor subtypes in longitudinal and circular muscle of human vas deferens.

The alpha1-adrenoceptor subtype(s) mediating contraction to noradrenaline in longitudinal and circular muscle of human epididymal vas deferens was studied using competitive antagonists. The effects of the alkylating agents, phenoxybenzamine and chloroethylclonidine were also investigated. Noradrenaline evoked concentration-dependent contractions of longitudinal and circular muscle with comparable potencies (pD2; 5.6 and 5.5 respectively). The contractions in longitudinal and circular muscle respectively were inhibited by prazosin (pA2, 8.6 and pKB, 9.2), 5-methylurapidil (pKB, 8.7 and 9.1) and less potently by spiperone (pA2, 7.1) or BMY 7378 (pKB, 6.3 and 6.6). Contractions of the circular but not longitudinal muscle was comparatively insensitive to pretreatment with phenoxybenzamine. In contrast pretreatment with chloroethylclonidine reduced the contractions in both muscle types and also enhanced phenoxybenzamine-sensitivity in longitudinal but not circular muscle. The results suggest that contractions evoked by noradrenaline in both muscle types of human vas deferens is mediated via activation of alpha1-adrenoceptors with pharmacological profile of the alpha1A-subtype. However the involvement of alpha1A-adrenoceptor variants, such as the hypothesised alpha1L-subtype may underlie the differential effects of phenoxybenzamine in longitudinal and circular muscle. Factors contributing to chloroethylclonidine-sensitivity are discussed.

The biochemistry of human endometrium after two regimens of postcoital contraception: a dl-norgestrel/ethinylestradiol combination or danazol.

A combination of 0.5 mg levonorgestrel (in 1 mg dl-norgestrel) and 0.1 mg ethinylestradiol was administered to eight volunteers 48 hours after the start of the luteinizing hormone surge. A second dose was given 12 hours later. Endometrial samples were obtained 24 hours after the first dose was given. The steroid receptor concentration was compared with ovulatory spontaneous cycles. The dl-norgestrel/ethinylestradiol combination caused a significant reduction in receptor concentration. Isocitrate dehydrogenase (a progestin-sensitive enzyme) was also altered, suggesting an effect on endometrial metabolism. Danazol was used in a similar fashion, with two doses each of 400 mg. Nine volunteers were studied. A similar pattern of alteration of endometrial biochemistry was demonstrated but did not reach statistical significance. The relevance to the postcoital use of hormones is discussed.

Influence of removal of intrauterine contraceptive devices on colonisation of the cervix by actinomyces-like organisms.

An overall prevalence rate of actinomyces-like organisms (ALO) in cervical smears from intrauterine contraceptive device (IUCD) users of 3% (79/2, 734) was found, with a rate of 2% and 22.6% for copper and inert IUCD users. Although the users of the inert IUCDs were older, and their devices had been in situ longer, these factors did not account for the significant difference between the two types of IUCD. Fifty-five patients were counselled and given a leaflet on ALO. Fourteen IUCD users with ALO positive smears who had their devices removed had mild or moderate pelvic pain or discharge. Six others who were asymptomatic had the IUCD removed at their own request. All fifty-five patients were re-examined six months to one year later, and a smear was repeated. Only one woman required later removal of the IUCD because of dyspareunia with pelvic tenderness. After removal of the IUCD, and without antibiotic therapy, in 100% (20/20) of the women, ALO colonisation was no longer found six to twelve months later. This applied even to seven women who had had a new copper IUCD inserted immediately after removal of the index device.

PIP: An overall prevalence rate of actinomyces-like organisms (ALO) in cervical smears of IUD users of 3% (79/2734) was found, with a rate of 2% and 22.6% for copper and inert IUD users. Although the users of the inert IUDs were older, and their devices had been in situ longer, these factors did not account for the significant differences between the 2 types of IUD. 55 patients were counseled and given a leaflet on ALO. 14 IUD users with ALO positive smears who had their devices removed had mild or moderate pelvic pain or discharge. 6 others who were asymptomatic had the IUD removed at their own request. All 55 patients were reexamined 6 months-1 year later and a smear was repeated. Only 1 woman required later removal of the IUD because of dyspareunia with pelvic tenderness. After IUD removal, and without antibiotic therapy, ALO colonization was no longer found 6-12 months later in 100% (20/20) of the cases. This even included the 7 women who had had new copper IUDs inserted immediately after removal of the index device.

Side effects of danazol compared with an ethinyloestradiol/norgestrel combination when used for postcoital contraception.

A postcoital contraceptive with a lower incidence of nausea and vomiting than oestrogen-progestogen combinations would be a significant advance. During a nine-month period, 101 women were treated at the Margaret Pyke Centre in London with either an oestrogen-progestogen combination or with danazol. A comparison of the side effects of each drug is reported. Those treated with danazol were six times less likely to experience nausea and none vomited. With the exception of breast symptoms, other side effects were five times less common in women receiving danazol. These differences give danazol a clear advantage in terms of patient acceptability. Further experience will enable the efficacy of danazol to be evaluated and so determine whether this drug should become the preferred hormonal postcoital treatment.

A possible mechanism of action of danazol and an ethinylestradiol/norgestrel combination used as postcoital contraceptive agents.

Twenty-seven women requesting postcoital contraception were randomly allocated to take an ethinylestradiol/dl-norgestrel combination or danazol. Urine specimens were assayed for luteinising hormone (LH) and pregnanediol-3-glucuronide (P3G) levels from the day of the postcoital treatment to the next period. In addition, the urine samples of these recruits and 12 additional women were assayed for the Beta-subunit of human chorionic gonadotropin (B-hCG). A consistent pattern of alteration in urinary steroids was lacking, indicating a heterogeneous effect on ovarian function. There was no evidence of early pregnancy in successfully treated cases. We suggest that the main mechanism of action of these drugs is at the endometrial level.

Effect of four combined oral contraceptives on blood pressure in the pill-free interval.

OBJECTIVE: To evaluate blood pressure changes in the pill-free interval and from baseline among women taking four different low-dose monophasic oral contraceptives. DESIGN: 131 women were randomized to four different oral contraceptives. Pressures were obtained at baseline, at the end of treatment cycles and at the end of the 7 pill-free days, during 6 months of treatment. Pressures were obtained at 4 and 8 weeks after discontinuation. Group 1 received norethisterone acetate 1000 micrograms, group 2 received levonorgestrel 150 micrograms, group 3 received desogestrel 150 micrograms, and group 4 received gestodene 75 micrograms, all combined with ethinyloestradiol 30 micrograms. RESULTS: All four groups showed an increase in pressure during treatment, with return to baseline levels four weeks after treatment. At the end of the pill-free interval, the readings did not differ significantly from on treatment except for women in Group 4, who experienced an increase in diastolic pressure. CONCLUSIONS: Use of the four oral contraceptives was associated with a small increase in systolic and diastolic pressure. Whatever mechanism causes the increase is not entirely reversible by 7 days without treatment.

PIP: The authors sought to evaluate blood pressure changes during the pill- free interval and from baseline among women taking 4 different low-dose monophasic oral contraceptives (OCs). 131 women were randomized to 4 different OC groups; pressures were obtained at baseline, at the end of treatment cycles, and at the end of the 7 pill-free days over 6 months of treatment. Pressures were obtained at 4 and 8 weeks after discontinuation. Group 1 received norethisterone acetate 1000 mcg, group 2 received levonorgestrel 150 mcg, group 3 received desogestrel 150 mcg, and group 4 received gestodene 75 mcg, all combined with ethinyl estradiol 30 mcg. All 4 groups showed an increase in pressure during treatment, with return to baseline levels 4 weeks after treatment. At the end of the pill-free interval, the readings did not differ significantly from those during treatment, except for women in group 4 who experienced an increase in diastolic pressure. Use of the 4 OCs was associated with a small increase in systolic and diastolic pressure. Whatever mechanism causes the increase is not entirely reversible after 7 days without treatment.

Changes in metabolism induced by oral contraceptives containing desogestrel and gestodene in older women.

Forty women aged 35-45 years were investigated to determine changes in haemostasis, lipids and lipoproteins whilst taking combined contraceptive pills containing the new third generation progestogens, desogestrel and gestodene. There was no statistically significant difference between the two preparations in any of the parameters studied. Women taking the combined pill showed increases in fibrinogen and factor X and a reduction in antithrombin III when compared with their control values. There were also small but significant increases in triglycerides and triglyceride-rich lipoproteins. Total high density lipoprotein cholesterol (HDL), high density lipoprotein-2 cholesterol (HDL2), high density lipoprotein-3 cholesterol (HDL3) and apolipoprotein A-1 were all increased at some stages of the treatment cycle, whereas low density lipoprotein cholesterol (LDL) showed a reduction in the first cycle of treatment. The changes in lipids and lipoproteins would not appear to increase the risk of cardiovascular disease, however the effects of the increase in the pro-coagulant factors are uncertain.

Hormonally impregnated intrauterine systems (IUSs), versus other forms of reversible contraceptives as effective methods of preventing pregnancy.

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.

Hormonally impregnated intrauterine systems (IUSs) versus other forms of reversible contraceptives as effective methods of preventing pregnancy.

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.

Preliminary report of unexpected local reactions to a progestogen-releasing contraceptive vaginal ring.

This is the first report of vaginal erythematous areas associated with the use of a levonorgestrel-releasing contraceptive ring. Of 139 female subjects, 48 developed lesions of varying size and degrees of redness. Sixteen of these have undergone serial colposcopy and thirteen have also had biopsy examinations, which revealed acetowhite areas and, histologically, chronic inflammation with widely dilated vessels and frequently with thinning of the epithelium. The cause remains uncertain but hormonal, chemical and physical effects might all have a role.

PIP: Between August 1990 and May 1992 in London, England, researchers enrolled 139 women aged 18-40 years in a clinical trial of a levonorgestrel-releasing contraceptive vaginal ring. All the women had a negative cervical smear. They underwent a thorough initial gynecological examination (i.e., visualization of entire vaginal area and the cervix). Clinicians reexamined them at 6 weeks, 3 months, and a 3-month intervals thereafter. 48 women (34.5%) had erythematous lesions on at least 1 occasion. They were at the vaginal vault, and sometimes on the cervix, where the vaginal ring usually lies. Most women had no symptoms. All the women were unaware that they had lesions. The lesions disappeared spontaneously in 16 women (33.3%) with the vaginal ring still in place. During colposcopy with vaginal ring in place, a clinician took vaginal/cervical swabs in 16 women to test for common sexually transmitted diseases (STDs). All but 1 woman tested negative for STDs. The erythematous lesion responded to 5% acetic acid in 14 of the 16 women, indicating an abnormality. Clinicians took biopsies in 13 of these women and did repeat colposcopy at 3-4 week intervals. Histological examination showed congestion with considerable dilated vessels, chronic inflammatory changes of varying severity, and frequent intracellular edema of the squamous mucosa. The mucosa was abnormally thin in some women, while in others it was entirely missing. Changes in 4 women were caused by HPV. 1 woman had grade 1 cervical intraepithelial neoplasia (CIN). The researchers could not conclude that the HPV-induced changes or CIN occurred during vaginal use because the women were not colposcoped before entry into the study. All of the study's findings prompted the ethics committee to halt the study in May 1992. In July 1992, the manufacturer shut down the entire UK study, stating that accumulation of enough data on efficacy and acceptability had been achieved. Further research is needed to determine what caused the lesions.

Intrauterine devices: present and future.

Although the mortality associated with the use of intrauterine contraception is low, its morbidity is probably higher than that associated with oral contraception. Much anxiety has been generated and whole programs prejudiced by lack of attention to detail during counseling, the fitting of intrauterine devices and follow-up. This paper draws attention to the shared etiology of many of the important adverse effects of the method, the fact that several become increasingly rare with increasing age of the user, and other factors that can assist in choosing the right device for the right woman. Likely future trends are also predicted.

PIP: Discussion focused on the adverse effects associated with IUDs and on the possibilities of developing new forms of IUDs capable of reducing these adverse effects. The most common adverse side effects associated with IUDs are ectopic pregnancy, miscarriage, failure due to expulsion, uterine perforation, infection, pain, bleeding, and subsequent infertility. Many of these problems stem ultimately from improper fitting and insertion procedures. Perforation is usually the direct result of improper insertion techniques and many pelvic infections occur shortly after insertion. The infection is 7.7/100 women years of use during the 1st 15 days following insertion, 2.2 during the 2nd year of use, and 0.7 during the 4th year of use. Hysterographic studies suggest that the improper position of IUDs is responsible for the high incidence of cramping, expulsion, and abnormal bleeding associated with IUD use. The risk of many of these negative effects is reduced with duration of use; however, most IUDs must be replaced every 2-3 years. As devices with longer life spans are perfected, some of the insertion related problems should decrease. Epidemiological research suggests that the long term use of copper IUDs is not carcinogenic; however, the long term use of plastic devices may be associated with an increased risk of actinomyces infection. Infection may also be introduced into the pelvic region via the IUD thread. Efforts are underway to develop IUDs with built in drug release control systems. These devices might reduce the incidence of infection. Efforts are also underway to develop IUDs which might reduce bleeding problems and other IUDs, such as the postpartum Delta T, which might reduce the postpartum expulsion rate.

The 150/30 formulation. Experience in the United Kingdom.

Oral contraceptive agents (OCs) containing levonorgestrel, 150 micrograms, and ethinyl estradiol, 30 micrograms, account for almost half the sales of such agents in the United Kingdom. The remarkable success of this formulation has occurred primarily because it provides extremely low doses of both hormonal constituents yet still gives most users a very acceptable bleeding pattern: the incidence of breakthrough bleeding is about 6% and of amenorrhea, less than 3%. Approximately 90% of users have cycle lengths of 28 +/- 3 days. The risk of serious side effects is significantly lower than with formulas containing higher doses of progestogen and/or estrogen. Minor side effects occur in only a small percentage of cycles. Headache is reported in approximately 10% of all cycles and should be regarded as a potential indicator of increased risk. If it presents as focal migraine, use of the combined OC should be discontinued. The contraceptive effectiveness of the 150/30 formulation is similar to that of the 50 micrograms formulations among compliant women; in less compliant women the margin of error is reduced, and the possibility of an increased risk of accidental pregnancy must be considered.

The diaphragm with and without spermicide. A randomized, comparative efficacy trial.

OBJECTIVE: To determine the relative contraceptive efficacy of a diaphragm used with spermicide as compared to one used without. STUDY DESIGN: Two hundred sixteen women entered the study between September 1985 and December 1990. Of these, 84 were randomly assigned to the diaphragm-only group and 80 to the diaphragm-with-spermicide group as their primary method of contraception. In addition, a spermicide-only group was planned originally to serve as a control group to assess the contribution to efficacy made by a spermicide alone. Thirty-nine women were randomly assigned to this group, and 13 selected themselves for it. All were followed for a maximum of 12 months. The primary outcome variable was accidental pregnancy. The statistical difference between the two diaphragm groups was analyzed. RESULTS: The 12-month "typical use" failure rates for the diaphragm-only group were 28.6 per 100 women and for the diaphragm-with-spermicide group, 21.2. The 12-month cumulative consistent-use failure rates were 19.3 per 100 women for the diaphragm-only group as compared to 12.3 per 100 women for users of a diaphragm with spermicide. CONCLUSION: Although the consistent use rates were not significantly different, this study had low statistical power and hence gives no support to the hypothesis that adjunctive spermicide use fails to improve the effectiveness of the diaphragm method, especially in view of the magnitude and direction of the difference observed. Unless a study with sufficient power proves that the use of a diaphragm alone is statistically as effective as use of a diaphragm with spermicide, use of a spermicide in conjunction with the diaphragm continues to be the appropriate clinical recommendation.

Comparison of four cytologic sampling techniques in a large family planning center.

In recent years, several new cervical sampling techniques have been introduced to try to improve the accuracy of the cervical smear. In the present study four such techniques were compared: the Aylesbury spatula, Rolon spatula, Cervex device and Aylesbury spatula used in conjunction with a Cytobrush. The total number of smears collected was 14,172, 80% of which were from women under age 35. Despite large differences between the techniques with regard to the presence of endocervical cells in smears, no differences were found in the detection of dysplasia. Endocervical cells were seen significantly more often in dysplastic smears than in negative smears. There was little difference in the rate of unsatisfactory samples. It appears that in a young population, the instruments used for cervical sampling are not likely to significantly influence the detection of dysplasia if skilled personnel take the smears.

Depot medroxyprogesterone and bone mineral density.

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.