Walli Bounds

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.

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.

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.

Observational series on women using the contraceptive Mirena ® concurrently with anti-epileptic and other enzyme-inducing drugs

Context Contraception for women on enzyme-inducing drugs. Objective To gather preliminary information on the contraceptive efficacy of the hormone-releasing intrauterine system (IUS) Mirena®, when used concurrently with enzyme-inducers. Design Observational series. Setting/participants Mirena® users on enzyme-inducers were recruited from within the Margaret Pyke Centre and via doctors from throughout the UK. Data were collected systematically on structured questionnaires with particular reference to duration of Mirena® use, exposure to pregnancy risk, type of concurrent medication, and reasons for drop-out. Main outcome measure Accidental pregnancies. Results To date, 56 women have provided follow-up information. Most took enzyme-inducers for epilepsy. They have accumulated 1454 months of use, of which 1075 months represent exposure to pregnancy risk. Only one apparently true Mirena® failure has been documented, representing a failure rate of 1.1 per 100 woman-years (95% CI 0.03-6.25). Including a second pregnancy, probably conceived after the Mirena® had been removed, would raise the failure rate to 2.2 per 100 woman-years (95% CI 0.27-8.07). Although 9/30 Mirena® removals were followed by re-insertion, only the first segment of use is analysed. Conclusion As this is a pilot study, no firm conclusions can be drawn, but our preliminary results suggest that any increased pregnancy risk, if it exists, falls within acceptable bounds.

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.

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.

Randomised controlled trial assessing the acceptability of GyneFix® versus Gyne-T380S® for emergency contraception

Objective To assess insertion-linked pain and the short-term user-acceptability and safety of the GyneFix® as compared with T-framed intrauterine devices (IUDs). Design A randomised controlled trial in an outpatient clinic setting. Method Women requesting an IUD for emergency contraception (EC) were allocated to either the short-term arm (GyneFix® versus Nova-T200®, or the long-term arm (GyneFix versus Gyne-T380S®, and then randomised within each group. Visual analogue scores were used to assess the womens perception of the pain associated with insertion, which was patient-blinded. Follow-up was double-blinded, at 6 weeks, with bleeding and pain recorded over this time. Results A total of 175 women received an IUD in the long-term arm. The short-term arm was discontinued due to low recruitment (17 women at 20 months) and therefore the results relate to the long-term arm only. Outcome was known in 98% of subjects. The actual insertion procedure was scored as more painful for the GyneFix, both by the women (p = 0.013) and the doctors making their assessment of the womens pain (p = 0.04). The women with GyneFix described less pain in the subsequent 30 days after insertion (p = 0.005). Only 13% of women with GyneFix requested removal as compared with 20% with Gyne-T380S, with the difference being attributed to removal due to pain. The bleeding pattern was similar for those using GyneFix and Gyne-T380S. Conclusions Our study suggests that although the actual fitting may be more painful, pain is less during the 6 weeks after insertion of GyneFix and fewer women discontinue its use because of pain, as compared with Gyne-T380S. The high overall continuation rate of all emergency IUDs at 6 weeks and low morbidity seen in this study favours more frequent IUD insertion where unprotected intercourse has occurred, given also its higher efficacy over oral hormonal EC.

Protein S levels are lower in women receiving desogestrel-containing combined oral contraceptives (COCs) than in women receiving levonorgestrel-containing COCs at steady state and on cross-over.

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 μg 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.

Comparative trial of the force required for, and pain of, removing GyneFix® versus Gyne-T380S® following randomised insertion

Objective To assess the force required for, and pain of, removal of the GyneFix® as compared with T-framed intrauterine devices (IUDs). Design A comparative trial following patient-blinded randomisation in an outpatient clinic setting. Method Women requesting an IUD for emergency contraception were fitted with either a GyneFix or a Gyne-T380S®. For those requesting removal of the IUD, visual analogue scores were used to assess their perception of the associated pain, and a Newton dynamometer was used to measure the force required to remove the device. Results Removal required significantly more force for GyneFix as compared with Gyne-T380S (p = 0.004), but there was no significant difference in pain perceived by women during removal. Interestingly, anticipated pain was worse than actual pain experienced. Conclusion Although more force is needed to remove the GyneFix as compared with the Gyne-T380S, this does not translate into more pain.

Medico-Legal Society Funds 2012 Health Watch Student Prize

Our future health-care professionals need training in the principles and practice of evidence-based treatments. We are all inundated with publicity in the media and internet about new and allegedly more effective treatments but which, on closer examination, are based on poorly designed clinical trials that could not possibly support the stated claims. Medical and nursing/midwifery students and allied professions need to be able to assess whether and how far such diagnostic or therapeutic claims for a particular treatment are valid to guide their clinical decisions. The 12th Annual HealthWatch Student Prize Competition (which this year was funded by the Medico-Legal Society) aims to determine whether these students have the essential skills to critically appraise clinical trial protocols and assess the validity of research findings.