Preregistration study on the safety and contraceptive efficacy of a progesterone-releasing vaginal ring in Chilean nursing women.

The contraceptive efficacy and safety of a progesterone-releasing vaginal ring (PVR) manufactured in Chile were compared to that of the Copper T 380A IUD (T-Cu) in nursing women enrolled at three Chilean clinics. A total of 285 volunteers chose to use the PVR and 262 the T-Cu. Plasma progesterone levels attained with the ring decreased from 25 to 14 nmol/L from month 1 to month 3 of use. Ring replacement was scheduled every 3 months. Volunteers continued in the study until weaning or completing the continuous use of four PVRs. No pregnancies occurred in 2320 and 2183 woman-months of exposure with the PVR and the T-Cu, respectively. Lower continuation rates in the first 6 months because of problems with use and a longer lactational amenorrhea were observed in the PVR than in the T-Cu group. Breast-feeding performance and infant growth were similar in both groups. These results confirm the high efficacy and safety of the PVR for nursing women and have led to the registration of the PVR by Chilean health authorities.

PIP: This study compares the contraceptive efficacy and safety of a progesterone-releasing vaginal ring (PVR) manufactured in Chile and a Copper T 380A IUD (T-Cu) in nursing women enrolled at three Chilean clinics. A total of 285 volunteers used the PVR and 262 used T-Cu. Plasma progesterone levels attained with the ring decreased from 25 to 14 nmol/l from month 1 to month 3 of use. Ring replacement was scheduled every 3 months. Volunteers continued in the study until weaning or completing the continuous use of 4 PVRs. There were no pregnancies in 2320 and 2183 woman-months of exposure with the PVR and the T-Cu, respectively. Lower continuation rates in the first 6 months because of problems with use and a longer lactational amenorrhea were seen in the PVR group. Breast-feeding performance and infant growth were similar in both groups. These results prove the high efficacy and safety of the PVR for nursing women. This has led to the registration of the PVR by Chilean health authorities.

[Information on advances in sciences and technology. Advances in contraceptive technology]. / Informacoes sobre avancos em ciencia e tecnologia. Avancos da tecnologia anticonceptiva.

PIP: Hormonal contraceptives include oral pills with lower steroid concentrations such as the triphasic gestodene. A dose of less than 20 mcg of ethinyl estradiol in the combined pill is effective. The use of RU-486 or mifepristone to inhibit ovulation or as a postcoital method is still being investigated. The vaginal rings that release 20 mcg of levonorgestrel (LNG) have a 97% rate of efficacy. There are newer types that release 30 mcg of LNG or desogestrel. A progesterone-releasing ring used during lactation is being studied. Among implants Norplant has been approved in many countries, including by the US Food and Drug Administration, with excellent results. In Brazil it continues to be banned. Studies have been initiated about implants, such as Norplant 11 and UNIPLANT. The studies conducted by the World Health Organization on injectables such as Cyclofem (which contains 5 mg of estradiol cypionate and 25 mg of medroxyprogesterone acetate) as well as Mesigyna (5 mg of estradiol valerate and 50 mg of norethindrone enanthate) are awaited. These two monthly injectables have minor side effects, produce regular cycles, and are highly effective. The use of GnRH analogues for ovulation inhibition are held back because of cost, dosage, and routes of administration The hormonal IUD releasing 20 mcg of LNG holds promise for high efficacy, probable protection against inflammations, and pronounced reduction of menstrual bleeding, particularly in long-term use. The frameless IUD, called Flexigard, consists of 6 fixed copper cylinders placed in the myometrium, which causes less endometrial irritation and less incidence of inflammation, pain, and bleeding. It has been in an experimental testing phase for some years. The female condom helps prevent STDs and is under the woman's control. Among male contraceptives, a hormonal method awaits development, while gossypol with the ability to inhibit HIV proliferation and the Chinese method of scalpel-free vasectomy are effective methods.^ieng

Evaluation of four different contraceptive vaginal rings: steroid serum levels, luteal activity, bleeding control and lipid profiles.

Four different models of contraceptive vaginal rings were tested during three cycles for luteal activity, bleeding control, plasma lipoproteins and serum levels of the contraceptive steroids. Two progestins, levonorgestrel acetate (LNGA) and ST 1435, alone or in combination with ethynyl-estradiol (EE) were tested. The rings released 100 ug/day of the progestins and 30 ug/day of EE. Luteal activity was detected among users of the progestin-only rings: 4 of 8 cycles with ST 1435 and 2 of 10 with LNGA. Only one of the 18 cycles studied with the two combined rings showed luteal activity, but the measurement of contraceptive steroid in plasma suggested that this subject delayed reinsertion of the ring for about one week in that particular cycle. Breakthrough bleeding was observed in 12 of 30 cycles of use of the progestin-only rings, and in only 2 of 27 cycles with the combined models. No significant changes in total cholesterol or its HDL-fraction were observed. However, the only reduction observed in HDL-cholesterol was among users of the LNGA-only ring. It is concluded that the two combined CVR models offer good possibilities of high effectiveness and bleeding control and merit further development.

PIP: Researchers analyzed data on 20 18-38 year old volunteers from the family planning clinic of PROFAMILIA in Santo Domingo, Dominican Republic, who had earlier undergone female sterilization to evaluate 4 different models of contraceptive vaginal rings during 3 cycles so as to identify which models would be the most likely to be an acceptable, safe, and effective family planning method. Women who used either of the 2 combined rings (ethinyl estradiol [EE] and either levonorgestrel acetate [LNGA] or ST 1435) had higher mean total serum levonorgestrel levels than those using the progestin-only rings (LNGA or ST 1435) (most were significant at .005). Luteal activity which marked ovulation was basically limited to users of the progestin-only rings (50% of cycles with ST 1435 and 20% of LNGA). It occurred in 1 of 18 cycles (5.6%) of users of combined rings (LNGA + EE). It probably occurred because of delayed insertion. The combined rings caused fewer incidents of breakthrough bleeding than did the progestin-only rings (7.4% vs. 40%). Neither the progestin-only nor the combined vaginal rings significantly altered total cholesterol or high density lipoprotein (HDL) levels. Users of the LNGA-only ring did experience an insignificant reduction in HDL, however. Further, triglycerides increased among users of the combined vaginal rings, but the increase was only significant with the LNGA + EE ring (25.4 mg/dl increase; p .05). Moreover, they fell significantly among users of the LNGA only ring (45.5 mg/dl decrease; p .05). The researchers concluded that the 2 combined rings hold the most promise due to good bleeding control and high effectiveness and therefore deserve further development.

[Menstrual blood loss and body iron stores: comparative study between a Multiload-375 IUD and a levonorgestrel vaginal ring]. / Perda sanguinea menstrual e estoques de ferro do organismo -- estudo comparativo entre o DIU Multiload-375 e o anel vaginal de levonorgestrel.

PIP: 107 users of vaginal rings and 74 users of Multiload-375 (ML-375) IUDs aged 18-40 years with more than 1 parity were studied. In the city of Santiago, Chile, 57 patients and at the University of Juiz de Fora, Brazil, 124 users were enrolled. The vaginal ring releases about 20 mcg/day of levonorgestrel (LNG). It was used continuously for 12 months with replacement every 3 months. The ML-375 was used continuously for 24 months or more. Menstrual blood loss (MBL) was determined before insertion; 3, 6, 9 and 12 months after insertion in both groups; and after 24 months in the IUD users. Serum ferritin measurement was done before use: 6 and 12 months after use in the vaginal ring group and 6, 12, and 24 after IUD insertion. Hemoglobin also was measured. It was observed that MBL always increased with IUD use and decreased with vaginal ring use. The measurements concerning IUD were significant in Santiago up to 24 months with a value of MBL of + 17.9 +or- 7.8 ml, while in Juiz de Fora they were significant up to 12 months returning to the value of preinsertion at 24 months (+ 3.1 +or- 4.6 ml). In vaginal ring users a small decrease of MBL was ascertained, but the only statistical difference occurred up to 12 months in Santiago (- 9 +or- 4.4 ml). In IUD use, in inverse correlation to MBL, serum ferritin dropped significantly at 6 months in Chile (- 7.7 +or- 2.9 ng.ml) and 6, 12, and 24-month follow-ups in Brazil (-5.2, -6 and-7.7 ng/ml, respectively). With the vaginal ring serum ferritin did not change significantly. These findings confirm previous research that ML IUDs increased MBL much less than other IUDs causing less change in iron stores even in patients with ferritin lower than 15 ng/ml, considered under the normal value. Yet for users in developing countries, the use of vaginal rings with LNG would be more suitable than the IUD ML-375 because of slighter alterations in the iron balance of the system.^ieng

Long-acting hormonal contraceptives for women.

Following the development and widespread use of oral hormonal contraceptives, it became evident that alternative long-acting delivery systems would be required to improve contraceptive practice in some cultural settings where injectable or subdermal routes of administration are preferred. Nowadays, long-acting contraceptives constitute an important option in family planning services in many parts of the world. Indeed, two long-acting injectable contraceptives containing just a synthetic progestogen (depot-medroxyprogesterone acetate (DMPA) and norethisterone enantate (NET-EN)) have been in clinical practice for more than 20 years. The World Health Organization's (WHO) Special Programme of Research in Human Reproduction, in collaboration with the U.S. National Institute of Child Health and Human Development (NICHD) and universities primarily in developing countries undertook a synthesis programme aimed at producing an improved injectable preparation by developing new derivatives of known steroids. One such compound (levonorgestrel 17-butanoate) is now at the stage of Phase II clinical testing. In addition, the Special Programme has developed and improved once-a-month injectable formulations and assessed their safety and efficacy in different countries worldwide. After large scale clinical testing, at least two progestogen-estrogen combinations have reached the point of introductory trials.

PIP: A survey of recent trials of new injectable hormonal contraceptives, progestogen-only, levonorgestrel esters, and once monthly injectables, follows a brief review of all the experimental long-acting contraceptive modalities, injectables, implants, vaginal rings, and hormone-releasing IUDs. Currently medroxyprogesterone acetate (DMPA) and norethisterone enanthate (NET-EN) are being used by 7 million women. WHO is conducting dose reduction trials and studies of bioavailability in various national populations. Even though a dose of 100 mg DMPA every 3 months has been satisfactory for contraception, 150 mg is still recommended until further pharmacodynamic data are available. Some populations, notably Thais and Mexican women, have higher peaks and more rapid elimination rates of DMPA, while Chinese women show slower elimination and higher blood levels of NET-EN. Extensive studies of new synthetic esters of levonorgestrel have proceeded to Phase II clinical trials with levonorgestrel butanoate. This ester is an effective contraceptive for 3 months at 12.5 mg, or 5-6 months at a dose of 25 or 50 mg. Trials of combined estrogen and progestogen injectables once-monthly have been ongoing for 10 years. The ratio of the 2 components is as important as the amounts. 2328 women from 12 countries participated in trials of DMPA 25 mg-estradiol cypionate 5 mg, and NET-EN 50 mg-estradiol valerate 5 mg. The continuation rate was better than that for 3-monthly progestogen-only injectables, because of less irregular bleeding. A combined injectable called Cyclofem, DMPA 25 mg-estradiol cypionate is being introduced in several countries. The steadily increasing demand for long-acting injectables prompts development of better formulations.

Determinants of menstrual bleeding patterns among women using natural and hormonal methods of contraception. I. Regional variations.

Records of the occurrence of vaginal bleeding were obtained from women using either a natural method of contraception or one of four types of hormonal contraceptive. The relationships between their bleeding patterns and a number of demographic variables were examined, with the aim of identifying subgroups of women who, if they used a particular hormonal method of contraception, would be likely to suffer more or less disruption to their bleeding pattern than the 'norm'. Within contraceptive method, bleeding patterns were more closely related to the women's geographical region of residence than to any other factor. Some of the differences between regions were consistent across contraceptive methods. European women tended to have more bleeding/spotting days than women in other regions; Latin American women had relatively short episodes and long bleeding-free intervals, whether they were using the ovulation method, combined pills or a vaginal ring. Other differences were method-specific. Women using combined pills in India or Pakistan had fewer spotting episodes than women using the same method elsewhere; those using progestogen-only pills had more. Regional variations in bleeding patterns were particularly marked among women using DMPA, and increased over time: by their fourth injection interval, 25% of European women had amenorrhea, as compared with 72% of subjects in North Africa. These findings need to be confirmed by carefully controlled studies of menstrual bleeding patterns and their acceptability in various ethnic groups. The results would be valuable in counselling new contraceptive acceptors, and could eventually guide the choice of methods for introduction into national family planning programmes.

The place of progesterone in human contraception.

Progesterone, the natural hormone produced by the corpus luteum and other steroid-secreting glands, is endowed with antiestrogenic action and has a fundamental role in the initiation and maintenance of pregnancy and in the regulation of gonadotropin secretion. Although it was discovered half a century ago, it has found little clinical use as a therapeutic agent due to its low potency and extensive degradation following oral administration in comparison with a variety of highly potent synthetic analogs that became available in the last three decades. When delivered systemically, a large proportion of the dose bypasses degradation in the gut and liver, and progesterone can achieve effective levels in target tissues for clinical use. Sustained administration via compressed pellets implanted subdermally or silicone rubber rings placed in the vagina produced circulating levels of progesterone within the lower third of those found in the luteal phase of the human menstrual cycle. Those levels were shown to delay the recovery of fertility in nursing women without adverse effects to the mother or the infant. Progesterone transferred to the babies via the breast milk did not change their rate of pregnandiol-3-alpha glucuronide excretion. It is concluded that sustained administration of the natural hormone progesterone may be an effective and safe contraceptive method for nursing women.

The hormonal ring. A new contraceptive gains acceptance.

PIP: The vaginal contraceptive ring under development by the Population Council's International Committee on Contraceptive Research (ICCR) is 58 mm in diameter and consists of a core of Salastic covered by a thin layer of levonorgestrel and estradiol with an overcoat of silicone rubber. The ring is inserted on the 5th day of the menstrual cycle and withdrawn 3 weeks later for 1 week. The steroids are released from the Silastic and readily absorbed through the vagina. The blood levels of contraceptive hormones are sufficient to prevent ovulation but do not display the great daily variation commonly observed in women on oral contraceptive (OCs). The ring contains sufficient hormones for 6 months of contraception. Preliminary research in developed countries indicates that the ring is as effective as and safer than the pill. In order to determine whether a method requiring twice monthly handling of the genitals and carrying a foreign body in the vagina for 3 weeks at a time would prove acceptable to poorer periurban and rural women in developing countries, the International Development Research Centre supported a study of the ring's acceptability in actual practice in Santo Domingo, Dominican Republic, and Campinas, Brazil. The ring was offered, with other methods, in several clinics in each country where prescription, instructions, and follow-up were provided by paramedical personnel. 150-200 ring acceptors in each country were to be compared with pill users, who were chosen for comparative purposes because both methods are hormonal, require the same sequence of use and rest, and tend to induce regular menses. Ring users were slightly older than pill users and tended to be better educated. 10% of ring users complained of difficulty with insertion, 20% of difficulty with removal, 43% worried about correct placement despite being told that the ring would work however inserted, 33% reported vaginal pain, and 10% reported having expelled it at some time. About half the women said the ring had changed color and about 1/3 of them did not like the change. Twice as many ring as pill users reported menstrual problems but 26% of pill users compared to 17% of ring users reported other problems such as headaches. 42% of ring users and 62% of pill users reported gaining weight. 17% of ring users and 7% of pill users considered their experiences "very good" but the general level of satisfaction with both methods was similar. An earlier study indicated that women liked having control over use of the method, inserting and removing the ring at will for intercourse or washing. The decreased amount and duration of menstrual bleeding was welcomed by most users, as was weight gain by some users.^ieng

User's perception of the contraceptive vaginal ring: a field study in Brazil and the Dominican Republic.

PIP: The basis for this report is home interviews of users of the contraceptive vaginal ring and the pill from urban and rural clinics in 2 provinces in the Dominican Republic and clinics from 2 towns and a large city in Brazil. Dominican ring users were significantly more likely to be older than pill users, to have more schooling, and have partners with more education. 6% were illiterate and 75% had only elementary education. 1/10 of the ring users reported having had problems with insertion of the ring and 1/5 had problems removing it. It may be worthwhile to try a narrower, more flexible model that may be easier to insert and remove. 1 out of every 6 users reported vaginal odor, 1 out of 8 reported having felt the ring move in their vagina, and 1/3 were aware of the ring at some time. About 1/2 the women in each country said the ring had changed color during use, and about 1/2 of those who reported the change did not like it. It became light gray and looked dirty. Correction may improve acceptance. 10% reported having expelled the ring. Twice as many ring users reported having menstrual problems. Ring and pill users both reported headaches, vaginal discharge, menstrual pain, and increased libido. A large proportion of ring and pill users experienced decreased duration and amount of menstrual bleeding, which was seen more as a beneficial than a negative effect. The same can be said for weight gain, which was "linked" by 89% of the women in the Dominican Republic. 64% of ring users and 67% of pill users described thier respective method as good or very good. Detailed instructions should accompany the final model. They should say that it is alright for the ring to be any place within tha vagina for it to be effective.^ieng

[The history of research on contraceptive methods in the Dominican Republic]. / Historia de la investigacion sobre metodos anticonceptivos en RD.

PIP: The Center for Investigation and Services in Human Reproduction and Contraception (CINSERHA), under the auspices of the Dominican association for Family Welfare (PROFAMILIA), conducts research in human reproduction and on the efficacy, effectiveness, seconardy effects, and other characteristics of contraceptive methods, as well as providing family planning services to more than 15,000 women each year. CINSERHA's research activities began in 1974 and have primarily involved development of Norplant subcutaneous implants, vaginal contraceptive rings, different models of IUDs, and male injectable methods. The most significant results to date have been contributions to the successful development and acceptance of the Norplant system, proff that IUDs do not entail "microabortions", and demonstration that the periovulatory period is the time of optimal conditions for sperm migration in the female genital tract. The objectives of CINSERHA studies are to develop new contraceptive methods, to achieve a better understanding of female physiology, and to explain the mechanisms of action of current contraceptive methods. CINSERHA participates in collaborative international studies with the US, Finland, Sweden, Chile, Brazil, and Jamaica under the leadership of the Population Council. 400 implants have been placed over 9 years and only 2 pregnancies have occurred, giving a failure rate of .4. The only side effect has been menstrual irregularity, which has tended to clear up with time. The only male method studied was a monthly injection of medroxyprogesterone and testosterone, which was abandoned as unpromising after 2 years of study. The cottonseed extract gossypol may be studied in the future, and studies on the vaginal ring have been successful except that some women complained of excessive vaginal discharge.^ieng

Lipoprotein patterns in women in Santo Domingo using a levonorgestrel/estradiol contraceptive ring.

Ten healthy, normally menstruating women attending a family planning clinic in Santo Domingo Participated in a study to determine the effects on plasma lipid levels of levonorgestrel and estradiol released from a contraceptive ring. A schedule of 21 days of use followed by 7 days of non-use was followed for 6 cycles. During the first two cycles of use, concentrations of cholesterol, HDL cholesterol, triglycerides and LDL cholesterol declined significantly from control levels, up to 25% for cholesterol, 28% for HDL cholesterol, 45% for friglycerides and 24% for LDL cholesterol. There were no subsequent changes with continued use. These declines are similar in direction but of lesser magnitude than those reported from clinics in other countries where pretreatment plasma levels of the same lipids are considerably higher. There was no significant change in the total cholesterol to HDL cholesterol ratio during treatment.

Acceptability of the contraceptive vaginal ring by rural and urban population in two Latin American countries.

A study of the field acceptability of the Contraceptive Vaginal Ring (CVR) was carried out in rural, small town and urban slum clinics in four locations, two in Brazil and two in the Dominican Republic (D.R.) The CVR was offered as a new method in the clinics and described as similar to the pill but placed in the vagina for three weeks each month with a one-week rest interval. Follow-up surveys were carried out in the four locations at the end of the experimental period. Three, eight, nine and 12.5% of the total acceptors in each of the 4 locations chose the CVR. The acceptance rate fell after the first five months but recovered during the second year. The acceptance rate was much higher in three rual clinics where the nurses themselves used the ring. The follow-up surveys showed that the fact that the ring is placed and kept in the vagina without removal for a prolonged period was the most important attribute of the method and played a large role in women's reactions to it. Anticipated use-related problems were the most prominent reason given by pill users for not choosing the ring, however ease of use was named as the "most killed" characteristic by 55% of ring users. Women tended to remove the ring for intercours and washed it frequently, often with detergents, thus illustrating their concern with "cleanliness" of an object kept within a body cavity for long periods of time.