Treatment of vaginal bleeding irregularities induced by progestin only contraceptives.

BACKGROUND: Despite their high effectiveness, progestin-only contraceptives are considered less than ideal by the many women who experience irregular vaginal bleeding when using them. Current treatments to control these bleeding problems are not sufficiently effective. OBJECTIVES: We evaluated preventive and therapeutic approaches to normalise bleeding irregularities associated with the use of progestin-only contraceptives. SEARCH STRATEGY: Literature was identified through database searches, reference lists, organisations and individuals, covering the period until December 2006. SELECTION CRITERIA: Trials with random or alternate allocation, testing interventions for the prevention or treatment of bleeding irregularities associated with the use of progestin-only contraceptives were eligible. DATA COLLECTION AND ANALYSIS: Results are expressed as relative risks (RR) with 95% confidence interval (CI) for categorical data and as weighted mean difference (WMD) with 95% CI for continuous data. When we encountered heterogeneity (visual or statistical) we used the random-effects model (quantitative) or did not produce a summary estimate (qualitative). MAIN RESULTS: Twenty three randomised controlled trials enrolling 2674 participants were included. Seventy per cent were determined to reflect low to moderate risk of bias. Estrogen treatments reduced the number of days of an ongoing bleeding episode in DMPA and Norplant users. However, treatment frequently led to study discontinuation due to gastrointestinal upset. Combinations of oral ethinyl estradiol and levonorgestrel improved bleeding patterns in Norplant users, but method discontinuation rates were unchanged. One trial reported successful use of combined oral contraceptives in treating amenorrhea among DMPA users. Norplant users, but not Implanon users, administered the anti-progestin mifepristone reported fewer days of bleeding than those given placebo. Mifepristone used monthly by new Norplant acceptors reduced bleeding, when compared to placebo.A variety of NSAIDS have been evaluated for their ability to treat abnormal bleeding, with mixed results. Norplant users receiving tamoxifen had less unacceptable bleeding after treatment and were more likely to continue using Norplant than those receiving placebo. Tranexamic acid, mifepristone combined with an estrogen and doxycycline were more effective than placebo in terminating an episode of bleeding in women using progestin-only contraceptives, according to three small studies. AUTHORS' CONCLUSIONS: Some women may benefit from the interventions described, particularly with cessation of current bleeding. Several regimens offer promise in regulating bleeding, but findings need to be reproduced in larger trials. The results of this review do not support routine clinical use of any of the regimens included in the trials, particularly for long-term effect.

Copper containing, framed intra-uterine devices for contraception.

BACKGROUND: Intrauterine devices (IUD) are safe and effective methods of long term reversible contraception. The design, and copper content as well as placement of the copper on IUDs could affect their effectiveness and side-effect profile. OBJECTIVES: We compared different copper IUDs for their effectiveness and side effects. SEARCH STRATEGY: Multiple electronic databases were searched with appropriate key words and names of the IUDs known to be in the market. We searched the reference lists of papers identified and contacted trialists when possible. There was no language restriction. SELECTION CRITERIA: Randomised controlled trials comparing different IUDs were considered. Trials needed to report on clinical outcomes. DATA COLLECTION AND ANALYSIS: Data on outcomes and trial characteristics were extracted in duplicate and independently by two reviewers. Meta-analysis results are expressed as rate difference (RD) using a fixed-effects model with 95% confidence interval (CI). In the presence of significant heterogeneity a random-effects model was applied. MAIN RESULTS: We included 35 trials, resulting in 18 comparisons of 10 different IUDs in approximately 48,000 women. TCu380A was more effective in preventing pregnancy than MLCu375 (RD 1.70%, 95% CI 0.07% to 2.95% after 4 years of use). TCu380A was also more effective than MLCu250, TCu220 and TCu200. There tended to be fewer pregnancies with TCu380S compared to TCu380A after the first year of use, a difference which was statistically significant in the fourth year (RD -1.62%, 95% CI -3.00% to -0.24%). This occurred despite more expulsions with TCu380S (RD 3.50%, 95% CI 0.36% to 6.63% at 4 years). MLCu375 was no more effective than TCu220 at 1 year of use, or MLCu250 and NovaT up to 3 years. Compared to TCu380A or TCu380S, none of the IUDs showed any benefits in terms of bleeding or pain, or any of the other reasons for early discontinuation. None of the trials that reported events at insertion found one IUD easier to insert than another or caused less pain at insertion. There is no evidence that uterine perforation rates vary by type of device. There are minimal randomised data on IUD use in nulliparous women. AUTHORS' CONCLUSIONS: TCu380A or TCu380S appear to be more effective than other IUDs. No IUD showed consistently lower removal rates for bleeding and pain in comparison to other IUDs. There is no evidence that any particular framed copper device is better suited to women who have not had children.

Treatment of vaginal bleeding irregularities induced by progestin only contraceptives.

BACKGROUND: Despite their high effectiveness, progestin-only contraceptives are considered less than ideal by the many women who experience disruption of their normal vaginal bleeding pattern when using these methods. Current treatments to control these bleeding irregularities are not sufficiently effective. OBJECTIVES: We evaluated preventive and therapeutic interventions of bleeding irregularities associated with the use of progestin-only contraceptives. SEARCH STRATEGY: Literature was identified through database searches, reference lists, organisations and individuals, covering the period until December 2006. SELECTION CRITERIA: Trials with random or alternate allocation, testing interventions for the prevention or treatment of bleeding irregularities associated with the use of progestin-only contraceptives were eligible. DATA COLLECTION AND ANALYSIS: Results are expressed as relative risks (RR) with 95 % confidence interval (CI) for categorical data and as weighted mean difference (WMD) with 95 % CI for continuous data. When we encountered heterogeneity (visual or statistical) we used the random-effects model (quantitative) or did not produce a summary estimate (qualitative). MAIN RESULTS: 19 Randomised controlled trials including 2290 participants were included. Over 60% of these trials had low to moderate risk of bias. Estrogen treatments reduced the number of days of an ongoing bleeding episode in DMPA users and had a positive therapeutic effect in Norplant users. However, treatment frequently led to discontinuation due to gastrointestinal upset. Combinations of oral ethinyl estradiol and levonorgestrel taken by Norplant users experiencing bleeding irregularities, improved bleeding patterns but method discontinuation rates remained the same. Norplant users administered the anti-progestin mifepristone therapeutically reported fewer days of bleeding than those given placebo. Prophylactic oral mifepristone used monthly by new Norplant users reduced bleeding, when compared to placebo.Ibuprofen was reported to decrease the length of bleeding episodes over a year, but the data were not presented in a suitable format for our analysis. Mefenamic acid reduced continued irregular bleeding during treatment in Norplant users, but not among DMPA users. Vitamin E and aspirin had no effect on bleeding patterns in a large trial of women using Norplant. Norplant users receiving tamoxifen had less unacceptable bleeding after treatment and were more likely to continue using Norplant than those receiving placebo. AUTHORS' CONCLUSIONS: Some women may benefit from the interventions described, particularly with cessation of an ongoing bleeding episode. Several regimens offer promise in regulating bleeding, but findings need to be reproduced in larger scale trials. Intermittent treatment with an agent may help some women to continue the use of a progestin-only contraceptive. The results of this review do not support routine clinical use of any of the regimens included in the trials, particularly for long-term effect.

Copper containing, framed intra-uterine devices for contraception.

BACKGROUND: Intrauterine devices (IUD) are safe and effective methods of long term reversible contraception. Design and copper content of IUDs could affect their effectiveness and side-effect profile. OBJECTIVES: We compared different copper IUDs for their effectiveness and side effects. SEARCH STRATEGY: Multiple electronic databases were searched with appropriate key words and names of the IUDs known to be in the market. We searched the reference lists of papers identified and contacted trialists when possible. SELECTION CRITERIA: Randomised controlled trials comparing different IUDs were considered. Trials needed to report on clinical outcomes. DATA COLLECTION AND ANALYSIS: Data on outcomes and trial characteristics were extracted in duplicate and independently by two reviewers. Meta-analysis results are expressed as rate difference (RD) using a fixed-effects model with 95% confidence interval (CI). In the presence of significant heterogeneity a random-effects model was applied. MAIN RESULTS: We included 34 trials, resulting in 16 comparisons of different IUDs. TCu380A was more effective than MLCu375, MLCu250, TCu220 and TCu200. Changing the position of the copper on the arm of the IUD for TCu380S did not improve the efficacy of TCu380A. MLCu375 was no more effective than TCu220, at 1 year, MLCu250 to 3 years or NovaT to 3 years Compared to TCu380A, none of the IUDs showed any benefits in terms of bleeding or pain, or any of the other reasons for early discontinuation. AUTHORS' CONCLUSIONS: TCu380A is more effective compared to other IUDs. There is no data available comparing different IUDs in special subgroups, such as nulliparous women.

Combination injectable contraceptives for contraception.

BACKGROUND: Combination injectable contraceptives provide a highly effective, reversible method of preventing pregnancy, and they do not require daily administration or use at the time of coitus. Although they are used in many countries, their acceptability could be limited by method characteristics, such as the need to obtain a monthly injection or bleeding pattern changes. OBJECTIVES: To assess the contraceptive efficacy, bleeding patterns, discontinuation, user preferences, and side effects of combination injectable contraceptives. SEARCH STRATEGY: We searched computerized databases for randomized controlled trials of combination injectable contraceptives. SELECTION CRITERIA: Randomized controlled trials reported in any language were eligible if they compared a combination injectable with any other contraceptive method (e.g., a second combination injectable contraceptive, progestin-only injectable contraceptive, other hormonal contraceptive or barrier method) or placebo. We limited the review to currently marketed combination injectable contraceptives. DATA COLLECTION AND ANALYSIS: The primary reviewer evaluated all titles and abstracts from the literature searches to determine their eligibility. Two reviewers independently extracted data from the eligible trials. Data on contraceptive efficacy, bleeding patterns, continuation, and side effects were entered and analyzed with RevMan 4.2. MAIN RESULTS: Combination injectable contraceptives include depot medroxyprogesterone acetate (DMPA) 25 mg plus estradiol cypionate (E(2)C) 5 mg, as well as norethisterone enanthate (NET-EN) 50 mg plus estradiol valerate (E(2)V) 5 mg. These combination injectable contraceptives resulted in lower rates of early study discontinuation due to amenorrhea or other bleeding problems, but had higher rates of discontinuation due to other reasons than the progestin-only comparison contraceptives. Studies comparing two combination injectable contraceptives found that NET-EN 50 mg plus E(2)V 5 mg resulted in less overall early discontinuation and less discontinuation due to amenorrhea or prolonged bleeding than DMPA 25 mg plus E(2)C 5 mg. However, these differences were not detected in all trials making this comparison. The NET-EN plus E(2)V group also had more cyclical (regular) bleeding and fewer prolonged bleeding reference periods than the DMPA plus E(2)C group. The groups did not differ in their amenorrhea rates. AUTHORS' CONCLUSIONS: While discontinuation rates can be viewed as a measure of method acceptability, the findings should be interpreted with caution since discontinuation rates are dependent on many other factors. Future research should be directed toward interventions to improve the acceptability of combination injectable contraceptives, such as providing injections in settings more convenient than clinical sites, methods for women to administer their own injections, and counseling about possible bleeding pattern changes.

Periodic abstinence and calendar method use in Hungary, Peru, the Philippines, and Sri Lanka.

Focus group research was conducted in four countries to understand how couples who use calendar methods determine when they are at risk of pregnancy, what behavior they adopt during the fertile phase, and whether or not they are satisfied with their method. Calendar and periodic abstinence method users do not all know how to make correct calendar calculations of the fertile period, report being sexually active during the fertile period, and desire a more comprehensive approach to sexual behavior during the fertile period. Men's roles in the methods should be enhanced, and credible resources in the community should be enlisted to improve education, information, and communication.

Delayed first injection of the once-a-month injectable contraceptive containing 25 mg of medroxyprogesterone acetate and 5 mg of E(2)-cypionate: effects on ovarian function.

OBJECTIVE: To assess whether women who were administered the first injection of DMPA+E(2)C on day 7 of their menstrual cycle (delayed injection) exhibit the same degree of ovarian suppression as women who receive it on day 5 of their menstrual cycle. DESIGN: Multicenter, randomized controlled trial. SETTING: Reproductive health clinics. PATIENT(S): Women aged between 18 and 38 years (inclusive) willing to use DMPA+E(2)C as their method of contraception. INTERVENTION(S): Participants received a DMPA+E(2)C injection on day 5 (control group, n = 41) or day 7 (delayed-injection group, n = 117) of their menstrual cycle. MAIN OUTCOME MEASURE(S): Ovarian activity and follicular development determined by serial serum progesterone levels and vaginal ultrasound. RESULT(S): Participants who received DMPA+E(2)C on day 5 of their menstrual cycle (control group) exhibited no more than limited follicular growth (no follicle >16 mm). Of those women who received DMPA+E(2)C on day 7 of their menstrual cycle (delayed-injection group), 21 (18%) showed some follicular growth, of whom 4 (3%) ovulated. CONCLUSION(S): The first injection of DMPA+E(2)C given on day 7 of a menstrual cycle does not provide the same inhibition of ovarian activity as that observed when it is administered on day 5 of the menstrual cycle.

Delayed first injection of the once-a-month injectable contraceptive containing 25 mg medroxyprogesterone acetate and 5 mg estradiol-cypionate: effects on cervical mucus.

The objectives of this study were to assess whether women who were administered the first injection of the once-a-month contraceptive containing estradiol cypionate and 25 mg depot-medroxyprogesterone acetate (MPA+E(2)C) on Day 7 of their menstrual cycle (delayed injection) exhibit the same degree of cervical mucus changes as women who receive it on Day 5 of their menstrual cycle. This was a multicenter, randomized, controlled clinical trial. A total of 158 women, aged between 18 and 38 years (inclusive), who, were willing to use MPA+E(2)C as their contraceptive method participated in the trial. Participants received a MPA+E(2)C injection on Day 5 (control group, n = 41) or Day 7 (delayed-injection group, n = 117) of their menstrual cycle. Participants who received MPA+E(2)C on Day 5 of their menstrual cycle (control group) exhibited fair or poor mucus quality and poor sperm penetration. Of those women who received MPA+E(2)C on Day 7 of their menstrual cycle (delayed-injection group), 3 (3%) showed good mucus or good sperm penetration at some time point during follow-up. It is possible to conclude that the first injection of MPA+E(2)C given on Day 7 of a menstrual cycle does not provide the same degree of inhibition of mucus quality and sperm penetration as that observed if it is administered on Day 5. However, the theoretical risk of pregnancy after receiving MPA+E(2)C on Day 7 would be expected to be low.

A randomized comparison of the effects on vaginal and cervical epithelium of a placebo vaginal ring with non-use of a ring.

Little is known about the effects of contraceptive vaginal rings on the vaginal surface epithelium, although most studies have not demonstrated any significant deleterious effect. However, one study found that some medium-to-long-term levonorgestrel-releasing ring users developed chronic erythematous and ulcerative lesions in the posterior vaginal fornix. Subsequently, this ring was completely redesigned (IVR-2) with different dimensions and much greater flexibility. The first version of IVR-2 was designed as a placebo ring to explore effects on the vagina and cervix without addition of a progestogen. One-hundred-sixty-six healthy sexually active women volunteers were recruited in four centers and randomly assigned for 6 months to either placebo ring use or control (non-use) using a predetermined randomization code generated by WHO in a 2:1 ratio. Careful inspections of the vaginal and cervical epithelium were performed with a colposcope at admission and at 2-month intervals. No clinically significant lesions were detected in any center either among ring users or controls. However, a number of minor changes in appearance of the vaginal and cervical epithelium (erythema, petechiae, ecchymosis, and minor aceto-white changes) were described from the Sydney Center, some of which were present on admission and some of which were found on subsequent examination. Ten of eleven "red" changes on the cervix and vagina were noted in IVR-2 users, and only one in the controls, suggesting a contribution by the IVR-2 to minor epithelial surface changes. Five of ten resolved completely with continued ring use. There was no correlation in this study between epithelial changes and cigarette smoking or frequency of intercourse in the 14 days prior to colposcopic examination but a significant relationship between tampon use in the last 7 days and all epithelial changes (p = 0.05) and especially red changes (p = 0. 027) was noted. Red changes were significantly less likely to be found among condom users (p = 0.007). The IVR-2 placebo ring did not produce clinically significant changes in the vaginal epithelium and cervical mucosa and a carefully controlled and randomized study should be considered to compare the epithelial appearances in women using a placebo IVR-2 and one releasing 20 microg levonorgestrel.

Management of vaginal bleeding irregularities induced by progestin-only contraceptives.

As the use of progestin-only methods of contraception continues to increase worldwide, the problem of the vaginal bleeding disturbances these methods induce is becoming of increasing public health relevance. A number of approaches are used by clinicians to control these bleeding irregularities but few treatments have been adequately tested and, to date, none appears sufficiently effective. Better understanding of the mechanisms underlying vaginal bleeding as well as of the attitudes of women towards menstrual disturbances is needed, so that effective and acceptable therapies can be devised.

Effectiveness of Cyclofem in the treatment of depot medroxyprogesterone acetate induced amenorrhea.

A total of 100 women who were using depot medroxyprogesterone acetate (DMPA) for contraception and who had experienced at least 6 months of drug induced amenorrhea, were randomized to either switching their method of contraception to Cyclofem, or continuing with DMPA. At the end of 6 months, 82% of the Cyclofem users had experienced some vaginal bleeding, compared with 10% of DMPA users. Time to resumption of vaginal bleeding was related to the duration of DMPA use to the duration of DMPA induced amenorrhea, and to the body mass index of the user. Over the 6 months of follow-up, 94% of Cyclofem users complained of some side effects, compared with 22% of DMPA users. The most frequently cited problems among Cyclofem users included breast tenderness, abdominal pain, and dysmenorrhea; yet a third of these women opted to stay on Cyclofem at the end of the study. It is concluded that switching to Cyclofem is a new option for DMPA users who are concerned about amenorrhea. Although using Cyclofem in this setting will not meet the needs of all such women, its effectiveness in inducing vaginal bleeding justifies a trial in those who have no contraindication to estrogen treatment.

PIP: Substantial numbers of women experience amenorrhea while using the injectable contraceptive depot medroxyprogesterone acetate (DMPA) and this represents a major cause of method discontinuation. In the present study, 100 DMPA acceptors from Bangkok, Thailand, with a history of at least 6 months of drug-induced amenorrhea were randomly assigned to switch their contraceptive method to Cyclofem (a combination of 25 mg of DMPA and 5 mg of estradiol cypionate) or continue with DMPA (150 mg). After 6 months, 82% of Cyclofem users compared with only 10% of DMPA users had experienced some vaginal bleeding. The median time to resumption of vaginal bleeding was 8 weeks in the Cyclofem group. Resumption time was related to the duration of DMPA use, the duration of DMPA-induced amenorrhea, and the user's body mass index. Although 94% of Cyclofem users compared with only 22% of DMPA users experienced minor side effects (breast tenderness, abdominal pain, dysmenorrhea) during the 6-month study period, 34% of these women elected to remain on Cyclofem at the end of the study. On the other hand, 90% of DMPA users opted to continue method use despite amenorrhea. The proven efficacy of Cyclofem justifies a trial in DMPA users concerned about their amenorrhea. This regimen can be expected to induce vaginal bleeding in more than 80% of users after 1-3 months of treatment.

Clinical evaluation of the therapeutic effectiveness of ethinyl oestradiol and oestrone sulphate on prolonged bleeding in women using depot medroxyprogesterone acetate for contraception. World Health Organization, Special Programme of Research, Development and Research Training in Human Reproduction, Task Force on Long-acting Systemic Agents for Fertility Regulation.

A placebo-controlled randomized clinical trial was conducted in six centres to compare the effects of a 14 day treatment with either 50 micrograms ethinyl oestradiol daily or 2.5 mg oestrone sulphate daily, on depot medroxyprogesterone acetate (DMPA)-induced prolonged bleeding. Out of 1035 women admitted to the study, 278 requested treatment and were given ethinyl oestradiol (n = 90), oestrone sulphate (n = 91) or placebo (n = 97). Ethinyl oestradiol was successful in stopping the bleeding episode in 93% of cases, compared with oestrone sulphate and placebo which had success rates of 76 and 74% respectively. However, the relative advantage of ethinyl oestradiol was marginal, with an average reduction of 1 bleeding day and 3 spotting days compared with the other two groups. Immediately after treatment, women given ethinyl oestradiol had less bleeding but a more unpredictable pattern than the other two groups. In the long term, there were no differences between the bleeding patterns or the discontinuation rates for any reason in the three groups, and the most important single reason for discontinuation in those groups remained 'menstrual problems'. In summary, the study showed that treatment of DMPA-induced prolonged bleeding with ethinyl oestradiol had a limited short-term effect but no beneficial effect on the acceptability of DMPA as a contraceptive method. Treatment with oestrone sulphate was no different from placebo.

PIP: The findings of a multicenter clinical trial challenge the practice of estrogen treatment of the prolonged or irregular vaginal bleeding associated with depot medroxyprogesterone acetate (DMPA) contraceptive use. Included in the study were 1035 DMPA users (mean age, 27 years) from Alexandria, Egypt; Bangkok, Thailand; Chiang Mai, Thailand; Jakarta, Indonesia; Karachi, Pakistan; and Manila, Philippines. 456 (44%) of these women experienced a bleeding episode lasting more than 7 days during their first 6 months of DMPA use. Of these, only 278 (61%) requested treatment. These 278 women were randomly allocated to receive 50 mcg of ethinyl estradiol (n = 90), 2.5 mg of estrone sulfate (n = 91), or placebo (n = 97) daily for 14 days. The treatment stopped the bleeding episode for 93% of women in the ethinyl estradiol group, 76% of those in the estrone sulfate group, and 74% of women receiving a placebo. The ethinyl estradiol advantage was marginal, however. On average, women treated with ethinyl estradiol had their bleeding episode shortened by 1 bleeding day and 3 spotting days. Immediately after treatment, women given ethinyl estradiol had less bleeding and spotting days than their counterparts in the 2 other groups, but demonstrated a more unpredictable pattern, including a greater range of lengths of bleeding/spotting-free intervals. Three months after treatment, there were no differences between the 3 groups in vaginal bleeding patterns.

Pharmacodynamic effects of depot-medroxyprogesterone acetate (DMPA) administered to lactating women on their male infants.

Normal postpartum women, who had a spontaneous vaginal delivery of one full-term male infant, free of congenital abnormalities and other diseases, were recruited for this study. Thirteen women received 150 mg depot-medroxy-progesterone acetate (DMPA), intramuscularly on days 42 + 1 and 126 + 1 postpartum. Infants of nine mothers, who did not receive DMPA, served as controls. Blood samples were collected from treated mothers on days 44, 47, 74, 124, 128, and 130 postpartum for medroxyprogesterone acetate (MPA) measurements. Four-hour urine collections were obtained from all 22 infants in the morning on days 38, 40, 42, 44, 46, 53, 60, 67, 74, 88, 102, 116, 122, 124, 126, 128, 130, and 137. Urinary follicle stimulating hormone (FSH), luteinizing hormone (LH), unconjugated testosterone, and unconjugated cortisol were measured by radioimmunoassay, and serum MPA and urinary MPA metabolites were measured by gas chromatography-mass spectrometry (GC-MS). No MPA metabolites could be detected in the urine of the infants from the DMPA-receiving mothers. Hormonal profiles in the urine samples were not suppressed in comparison with those of the control infants. The present study demonstrates that DMPA, administered to the mother, does not influence the hormonal regulation of the breast-fed normal male infant.

A review of "once-a-month" combined injectable contraceptives.

PIP: The once-a-month combined progestogen and estrogen injectables were developed to overcome menstrual irregularity, a major reason for discontinuation of progestogen-only contraceptives. About 2 million women have already used the combined once-a-month injectables, particularly in Latin America and China. The currently available once-a-month combined injectable contraceptives are Chinese Injectable No. 1 (17 alpha-hydroxyprogesterone caproate, estradiol valerate), another formulation marketed under various brand names in Latin America (dihydroxyprogesterone acetophenide, estradiol enanthate), Cyclofem (medroxyprogesterone acetate [MPA], estradiol cypionate), Mesigyna (norethisterone enanthate, estradiol valerate), and Mego-E (megestrol acetate, 17 beta-estradiol). Cyclofem and Mesigyna are very effective at preventing pregnancy (1-year rate, 99.8-99.6%). The rate for the dihydroxyprogesterone acetophenide/estradiol enanthate formulation is 100%, while that for Chinese Injectable No. 1 is 94%. Even though menstrual disturbances occur less often in once-a-month injectable users, they are the leading medical reason for discontinuation. At 1 year of use, about 70% of Cyclofem and Mesigyna users have regular bleeding patterns compared to 8% of Depo-Provera users. None of the Cyclofem and Mesigyna studies have found them to induce any adverse or clinically relevant metabolic changes. Once-a-month combined estrogen and progestogen injectables do not cause any significant delay in return to ovulation, but researchers should collect more data on conception rates for women who discontinue for planned pregnancy and those who discontinue for bleeding disorders and amenorrhea. Research into service delivery of these injectables is needed to assess managerial requirements or adaptations that would be required should there be more wide scale introduction of a contraceptive into both public and private sectors. Age, contraceptive history, learning about injectables and husbands' attitude, and knowing another user's satisfaction with the service appear to be important determinants of acceptability of once-a-month injectables.^ieng

Once-a-month injectable contraceptives.

PIP: Two long-acting injectable progestogen-only preparations, DMPA and NET-EN, have been used for many years, but produce unpredictable and often unacceptable bleeding patterns. Combined progestogen/estrogen preparations which are equally effective, yet capable of yielding more predictable menstrual patterns have therefore been under development. Cyclofem and Mesigyna are two such preparations which have recently become available. Cyclofem contains 25 mg medroxyprogesterone acetate and 5 mg estradiol cypionate, while Mesigyna is comprised of 50 mg norethisterone enanthate and 5 mg estradiol valerate. The World Health Organization reviewed available toxicological data on DMPA and NET-EN in 1982 and found the agents to be safe for human use. A group of experts convened at the behest of the World Health Organization, June 1993, reviewed these more recent formulations to find them safe and effective reversible products for fertility regulation which can be added to the existing range of contraceptive methods. Cyclofem and Mesigyna can be used by all potential contraceptive users provided that precautions are taken to assess potential risk factors. They are highly effective, have a low incidence of side-effects, and offer vaginal bleeding patterns which are better than those seen with progestogen-only injectables.^ieng

Once-a-month estrogen/progestogen injectables.

PIP: About 8 million women use the long acting injectable contraceptive depot-medroxy-progesterone acetate (DMPA) and norethisterone enanthate (NET-EN). These progesterone only injectables are not dependent on sexual activity and are easy to administer. Yet they are not always well accepted since they can interfere with menstrual bleeding and often induce amenorrhea. Researchers find that adding estrogen to DMPA and NET-EN treats these irregularities. They must use esters with limited action to protect the endometrium from constant estrogens, however, which requires monthly injections. Thus bleeding occurs once a month just like the normal menstrual cycle. Clinical trials in China of Injectable No. 1 (250 mg 17-alpha-hydroxyprogesterone caproate and 5 mg estradiol valerate) show that it has few side effects and is acceptable. Other trials in China are evaluating monthly injectables with NET-EN or megestrol acetate. Numerous developing countries often as WHO's Special Programme of Research in Human Reproduction for effective, safe, and fully studied monthly injectables. WHO operates under a 2 part strategy: optimum improvement of HPR 102 (50 m NET-EN and 5 mg estradiol valerate) and Cyclofem (25 mg DMPA and 5 mg estradiol cypionate) resulting in a reduction of the dose of at least 1 of the hormones and results of a study of the efficacy and side effects of these 2 injectables. It hopes the study provides the impetus to introduce them into national family planning programs. It demonstrates that they are indeed efficacious, effect fewer changes in the menstrual cycle than the progesterone only injectables, and are well accepted, even though women must go to a clinic every 27-33 days for an injection. Other studies are determining their effects on lipid and glucose metabolism, coagulation, and fibrinolysis. They are also looking at the time needed for ovulation to return. 1 study shows that menstruation returned in all women by the 3rd cycle.^ieng

Prostaglandin production in human endometrium following continuous exposure to low-dose levonorgestrel released from a vaginal ring.

Arachidonic acid metabolites produced by primary cultures of human endometrial cells derived from biopsies obtained before and after exposure to 20 micrograms/day levonorgestrel for 84 +/- 1 days were analysed by reverse phase HPLC. This revealed a significant increase in PGF1 alpha and an epoxide metabolite upon levonorgestrel stimulation. The proportion of epoxide metabolite, PGF1 alpha and PGE2 were positively correlated with serum levonorgestrel levels while HETES, PGE2 and epoxide were similarly correlated with serum oestradiol. The extent of intermenstrual bleeding during exposure to levonorgestrel was correlated with the proportion of epoxide and HETES products in vitro which is discussed in relation to their physiological function.

PIP: Reverse phase high-performance liquid chromatography was used to analyze arachidonic acid metabolites produced by human endometrial cell cultures before and after long-term exposure to 20 mg/day of levonorgestrel released from a released from a vaginal ring. Biopsy specimens were obtained on day 24 of a control menstrual cycle and again 84 days after insertion of the vaginal ring. Significant changes resulting from levonorgestrel exposure were recorded in only 2 of the 14 products of synthesis resolved--6-keto-prostaglandin F 1-alpha at 24 hours and epoxide at 48 hours. There were dose-dependent decreases in all cyclo-oxygenase products and an increase in epoxygenase enzyme levels. Hydroxyeicosatetraenoic acid (HETES) production, on the other hand, was strongly associated with estradiol and thus appears to be under estrogenic control. Intermenstrual bleeding during the study period was correlated with the proportion of epoxide and HETES products in vitro. Investigation of the role of the epoxygenase metabolite identified in this study in the regulation of uterine vasculature is urged.

Morphometric study of the human endometrium following continuous exposure to levonorgestrel released from vaginal rings during 90 days.

The effects of vaginal devices releasing levonorgestrel (LNG) at a constant rate of approximately 20 micrograms/24 hrs on the human endometrium were studied in a group of 69 normally menstruating women during a period of 90 days of continuous use. Peripheral blood samples were withdrawn three times weekly starting at day 10 of a pretreatment (control) cycle and then three times weekly from day 60 to 90 of the treatment period. The levels of LNG, estradiol, progesterone and sex hormone binding globulin (SHBG) were analyzed by radioimmunoassay techniques. Endometrial biopsies were obtained in the luteal phase of the pretreatment cycle and on day 84-87 of the treatment period. Increased bleeding occurred in most subjects exposed to the LNG-releasing device; the mean number of bleeding and spotting days was 26.4 +/- 8.9 S.D. which exceeded that found in their control cycle. Morphometric analyses of the endometrial biopsies using 9 quantitative indices, revealed highly significant changes in glands and stroma following the use of the LNG-releasing vaginal device. Irrespective of the circulating steroid levels, the administration of LNG significantly diminished the glandular diameter (p less than 0.001), reduced the volume density of the glands (p less than 0.001) and of the glandular epithelium (p less than 0.001). and modified the ratio glandular epithelium: glands (p less than 0.001). It is concluded that levonorgestrel released at a rate of 20 micrograms/24 hrs, induces characteristic changes in the histologic structure of the human endometrium. Although no simple correlation has been found between any of the endometrial indices and the numbers of bleeding/spotting days or bleeding days, the changes as such may represent biochemical alterations which could be predisposing factors for intermenstrual bleeding and spotting. To prove a causal relationship between morphological and biochemical changes and changes in bleeding patterns, further in-depth studies may be required.

Coping with extra Poisson variability in the analysis of factors influencing vaginal ring expulsions.

The vaginal ring is one method of contraception currently under investigation and development by the Human Reproduction Programme of WHO. One factor that reduces its acceptability is that some women experience involuntary expulsions of the ring. WHO have collected prospective data on 1005 women from 19 centres worldwide to investigate various aspects of ring use including factors that might affect expulsions. For each subject the data include number of expulsions, age, parity, ponderal index, number of days of ring use and health care centre. To model the factors influencing expulsion, the number of expulsions was first considered as a Poisson variate with mean directly proportional to the log of the duration of ring use. Such a model gave a poor description of the data and it appeared that the number of expulsions was considerably over-dispersed for an assumed Poisson variate. This paper examines a variety of strategies for coping with the resulting lack of fit of the model. It turns out that a truncated Poisson model gives a better description of the expulsion data and that health care centre and parity influence the rates.