Gossypol blood levels and inhibition of spermatogenesis in men taking gossypol as a contraceptive. A multicenter, international, dose-finding study.

The safety and efficacy of gossypol continues to be controversial. The aim of this study was to evaluate gossypol as a contraceptive pill for men at doses lower than those previously prescribed and in men from various ethnic origin. A total of 151 men from Brazil, Nigeria, Kenya, and China were divided into two groups. Both groups received 15 mg gossypol/day for 12 or 16 weeks to reach spermatogenesis suppression. Subjects were then randomized to either 7.5 or 10 mg/day for 40 weeks. In addition, 51 men were enrolled as a control group. In all, 81 subjects attained spermatogenesis suppression. Only one man discontinued treatment because of tiredness. Potassium levels fluctuated within the normal range. FSH increased consistently. Testicular volume decreased, but after discontinuation, values returned to levels not statistically different from admission. Of 19 subjects on the 7.5 mg/day dose group, 12 recovered sperm counts >20 million/mL within 12 months of discontinuing gossypol. In the 10 mg/day group, sperm counts recovered in only 10 of 24 subjects. Eight of the 43 patients remained azoospermic 1 year after stopping gossypol. All men diagnosed with varicocele failed to reverse spermatogenesis suppression. Gossypol blood levels indicated that sperm suppression occurs independently of concentration, whereas spermatogenesis recovery appears to be concentration-dependent. Gossypol may become a medical alternative to surgical vasectomy when the delay in onset of infertility is acceptable. When taken for 1 year, gossypol causes no reduction in sexual desire or frequency of intercourse. The possibility of reversal, occurring in 51% of the men on this regimen within 1 year after stopping gossypol, is an advantage of this compound as compared with surgical sterilization in many parts of the world.

PIP: The safety and efficacy of gossypol continues to be controversial. The aim of this study was to evaluate gossypol as a contraceptive pill for men at doses lower than those previously prescribed and in men from various ethnic origin. A total of 151 men from Brazil, Nigeria, Kenya, and China were divided into two groups. Both groups received 15 mg gossypol/day for 12 or 16 weeks to reach spermatogenesis suppression. Subjects were then randomized to either 7.5 or 10 mg/day for 40 weeks. In addition, 51 men were enrolled as a control group. In all, 81 subjects attained spermatogenesis suppression. Only 1 man discontinued treatment because of tiredness. Potassium levels fluctuated within the normal range. FSH increased consistently. Testicular volume decreased, but after discontinuation, values returned to levels not statistically different from admission. Of 19 subjects in the 7.5 mg/day dose group, 12 recovered sperm counts higher than 20 million/ml within 12 months of discontinuing gossypol. In the 10 mg/day group, sperm counts recovered in only 10 of 24 subjects. 8 of the 43 patients remained azoospermic 1 year after stopping gossypol. All men diagnosed with varicocele failed to reverse spermatogenesis suppression. Gossypol blood levels indicated that sperm suppression occurs independently of concentration, whereas spermatogenesis recovery appears to be concentration-dependent. Gossypol may become a medical alternative to surgical vasectomy when the delay in onset of infertility is acceptable. When taken for 1 year, gossypol causes no reduction in sexual desire or frequency of intercourse. The possibility of reversal, occurring in 51% of the men on this regimen within 1 year after stopping gossypol, is an advantage of this compound as compared with surgical sterilization in many parts of the world.

Effects of long-term low-dose mifepristone on reproductive function in women.

Low-dose antiprogestin administration has been proposed as a new contraceptive modality to interference with endometrial receptivity without disturbing ovarian function. The effects of 1 mg/day mifepristone for 150 days on the menstrual cycle were assessed in 21 surgically sterilized women. The aim was to study each woman for one control cycle and during months 1, 3 and 5 of treatment. Ovulation, endometrial thickness, serum oestradiol and progesterone, urinary luteinizing hormone, endometrial morphology and cervical mucus were assessed. Luteal phase progesterone concentrations were observed in 36 of the 60 treated months assessed and less frequently as treatment progressed. The bleeding pattern was regular in most biphasic cycles, while prolonged interbleeding intervals or no bleeding were associated with monophasic cycles. Altered endometrial morphology was found in all cases irrespective of the occurrence of luteal activity. Increased endometrial thickness and dilated glands were observed in 25 and 34% respectively of the monophasic cycles. Mifepristone, 1 mg/day, interferes with endometrial development while allowing the occurrence of biphasic ovarian cycles and regular bleeding. However, it also prevents ovarian cyclicity in a high proportion of treated months, and this is associated with increased endometrial growth in some women, which may be of concern.

PIP: Low-dose antiprogestin administration has been proposed as a new contraceptive modality that interferes with endometrial receptivity without disturbing ovarian function. To explore this potential, the effects on the menstrual cycle of 1 mg/day of mifepristone for 150 days were assessed in 21 surgically sterilized women from Santiago, Chile. Control cycles were biphasic in all 21 women and ovulatory in 20 women. Luteal phase progesterone concentrations were observed in 36 of the 60 treatment months (1, 3, and 5) assessed. The proportion of ovulatory cycles was highest during month 1 and decreased progressively with treatment. 40% of treatment cycles were monophasic and bleeding cyclicity was altered in 57%. Prolonged inter-bleeding intervals or no bleeding occurred in monophasic cycles. Endometrial morphology was altered in all cases, regardless of the occurrence of luteal activity. Increased endometrial thickness and dilated glands were recorded in 25% and 34%, respectively, of the monophasic cycles. These findings suggest that 1 mg of mifepristone interferes with endometrial development while allowing biphasic ovarian cycles and regular bleeding. Whether these endometrial alterations are sufficient to prevent implantation remains to be established. The long-term effect of prevention of ovarian cyclicity and the associated increased endometrial growth recorded in some women require further investigation.

Contraceptive potential of a mifepristone-nomegestrol acetate sequential regimen in women.

The effectiveness of a sequential regimen consisting of mifepristone, 10 mg/day for 15 days, followed by nomegestrol acetate (NOMA), 5 mg/day for the next 13 days, for inhibiting ovulation and maintaining regular bleeding cycles was assessed in 10 surgically sterilized volunteers who were followed for one pretreatment and three treated cycles. Hormonal determinations in blood and urine, ovarian ultrasonography, bleeding records in all cycles and an endometrial biopsy taken on day 22-25 of the third treatment cycle were used to monitor the effects of treatment. During treatment, 24 monophasic (no sustained progesterone rise above 12 nmol/l) and six biphasic cycles were recorded. Nine follicular ruptures were detected echographically in these 30 treated cycles, five of which occurred in monophasic cycles. All follicular ruptures occurred on days 1-7 of NOMA treatment. Echographic and endocrine features of ovulatory cycles were both present in only four treated cycles (13.3%). Development of a secretory endometrium was achieved in all cases, but it was always irregular. Regular withdrawal bleeding occurred in all subjects and no adverse reactions were recorded. The ovarian and endometrial effects of this regimen justify testing its contraceptive effectiveness in phase 2 clinical trials.

PIP: This study investigated the efficacy of mifepristone, 10 mg/day for 15 days, followed by nomegestrol acetate (NOMA), 5 mg/day for the next 13 days, for inhibiting ovulation and maintaining regular bleeding cycles in 10 surgically sterilized volunteers. To monitor the effects of treatment, hormonal determinations in blood and urine, ovarian ultrasonography, bleeding records in all cycles and endometrial biopsy were taken on day 22-25 of the third treatment cycle. About 24 monophasic and 6 biphasic cycles were recorded during treatment. About 9 follicular ruptures were echographically detected in these 30 cycles, 5 of which occurred in monophasic cycle. All follicular ruptures occurred in days 1-7 of NOMA treatment. Echographic and endocrine features of ovulatory cycles were both present in only four treated cycles (13.3%). Development of a secretory endometrium was achieved in all cases, but it was always irregular. Regular withdrawal bleeding occurred in all subjects and no adverse reactions were observed. The ovarian and endometrial effects of this regimen justify testing its contraceptive effectiveness in phase 2 clinical trials.

Contraception with two levonorgestrel rod implants. A 5-year study in the United States and Dominican Republic.

A 5-year trial of a two-rod contraceptive implant, which releases the progestin levonorgestrel (LNG rod), was conducted at four clinics with 594 women. Mean age and weight at admission were 25.5 years and 62.4 kg, respectively. Consent to continue through 5 years was sought and obtained when the 3-year cumulative pregnancy rate proved to be 0.8 per 100. No pregnancies occurred in the fourth or fifth years. The 5-year cumulative pregnancy rate was, therefore, 0.8 per 100 with an annual average pregnancy rate below 2 per 1000 women. Prolonged bleeding/spotting (8.2% of subjects) and irregular bleeding (5.6%) were the most frequently cited medical reasons for removal. Removals for headache (4.7%) and weight change (4.0%) were the next most frequent medical reasons. Between 1% and 2% of subjects during the 5-year trial sought removals for each of the following conditions: mood changes, lower abdominal pain, depression, or pain at the implant site. The mean annual continuation rate during the study was 77 per 100. Use per woman averaged 2.96 years. Mean removal time was 5.9 +/- 0.6 min. These data indicate that, for a 5-year period, the two LNG rod implants are equivalent to the six Norplant capsule implants with respect to safety and efficacy parameters, but permit easier and more rapid implant removal.

PIP: The newly developed 2-rod levonorgestrel (LNG) implant system has a surface area only 44% that of Norplant yet provides LNG release rates and blood levels similar to the 6-capsule Norplant system. Clinical trials of the 2-rod implant system initiated in 1990 demonstrated an exceptionally low cumulative pregnancy rate (0.8/100) in the first 3 years of use. This paper reports on an extension of the original study for an additional 2 years. 594 women at 4 study sites in the US and the Dominican Republic completed 5 years of method use. No pregnancies occurred in the fourth and fifth years of use. Thus, the 5-year cumulative pregnancy rate was 0.8/100, with an average annual pregnancy rate below 2/1000 women. The mean annual continuation rate during the 5-year study period was 77/100 women, with an average duration of use of 2.96 years. The most frequent reasons for medical removal were prolonged bleeding/spotting (8.2% of women), irregular bleeding (5.6%), headache (4.7%), and weight gain (4.0%). Mean removal time was 5.9 minutes and complications occurred in only 2.3% of removals. Overall, these findings confirm that the 2-rod LNG implant contraceptive has an effectiveness equivalent to the 6-capsule implant for a 5-year period, with good acceptability and a substantially improved ease of removal.

Fertility impairment after mifepristone treatment to rats at proestrus. Actions on the hypothalamic-hypophyseal-ovarian axis.

Accumulated evidence indicates that the antigestagen mifepristone affects the reproductive axis acting on hypothalamic, pituitary, ovarian, and uterine tissues. The purpose of this study was to further investigate which reproductive functions are impaired by the antagonist, critically compromising the reproductive process, leading to unsuccessful pregnancy. Circulating pituitary and ovarian hormones, sexual receptivity, ovulation, and implantation rates were studied in cycling rats receiving a single dose of mifepristone (1 or 10 mg/kg subcutaneously) at 12:00 proestrus, before luteinizing hormone (LH) stimulation of the ovulatory process. Mifepristone-treated rats had decreased preovulatory surges of LH and prolactin (PRL), and hypersecretion of LH, PRL, and progesterone at estrus. The sexual receptivity was dramatically affected by the antagonist as indicated by the profound decrease in the lordosis response evaluated on the night of proestrus. The number of ovulating animals and the number of oocytes recovered from the oviduct on the morning of estrus were not affected by mifepristone. The low number of rats that succeeded in mating with potent males became pregnant. However, they delivered an average of only two pups at parturition, indicating a failure in the implantation of the fertilized ova, as ovulation was not affected by the antagonist at the dose used. We conclude that a dramatic inhibition of the sexual receptivity and unsuccessful implantation, preceded by a reduction on LH and PRL secretion, are the major components leading to fertility impairment after a single dose of mifepristone administered before the preovulatory surge of LH.

PIP: Mifepristone has been demonstrated to act on hypothalamic, pituitary, ovarian, and uterine tissue. To further investigate impairments in reproductive function triggered by this antagonist, circulating pituitary and ovarian hormones, sexual receptivity, ovulation, and implantation rates were studied in cycling Wistar rats receiving a single dose (1 or 10 mg/kg subcutaneously) of mifepristone at 12:00 proestrus, before luteinizing hormone (LH) stimulation of the ovulatory process. Treated rats had decreased preovulatory LH and prolactin (PRL) surges and hypersecretion of LH, PRL, and progesterone as estrus. A profound decrease in the lordosis response on the night of proestrus indicated a dramatic effect on sexual receptivity. There was no affect on the number of ovulating animals and the number of oocytes recovered from the oviduct on the morning of estrus. The few rats who succeeded in mating with potent males became pregnant, but they delivered an average of only two pups, indicating a failure in the implantation of the fertilized ova. These findings suggest that the dramatic inhibition of sexual receptivity and unsuccessful implantation, preceded by a reduction in LH and PRL secretion, are the major factors producing fertility impairment after a single dose of mifepristone before the preovulatory LH surge. factors such as smoking and parity.

Temporal relationship between Uniplant insertion and changes in cervical mucus.

This study was undertaken to determine the time required by a single implant containing nomegestrol acetate to affect cervical mucus production and sperm penetration in women. All subjects were investigated and, if necessary, treated for any kind of cervicitis or vaginitis prior to starting cervical mucus study. The subjects had not used hormonal contraception for at least three months prior to investigation. They were counseled to use condoms during this study and also to refrain from intercourse during the period of cervical mucus sampling. Follicular development and endometrial thickness were analyzed by transvaginal sonography. Cervical mucus examination, sperm penetration test, and transvaginal sonography were performed during the control cycle and during the first cycle of Uniplant use. Blood samples were taken for the measurement of estradiol, LH, and progesterone. Cervical mucus and sperm penetration tests were evaluated according to the World Health Organization (WHO) criteria. In the treated cycle, when cervical mucus reached a score of 8-10, Uniplant was inserted, independent of the day of the cycle. Cervical mucus was then collected at 0, 4, 8, 12, 24, 48, and 96 h later until a marked change in volume, consistency, ferning spinnbarkheit, and cellularity was observed. All samples were also used for sperm penetration test. Preovulatory estradiol and LH peak decreased significantly compared to pre-implant insertion. Progesterone levels were within the normal limit. Cervical mucus and sperm penetration tests were not affected by Uniplant in the first 12 h. Twenty-four hours after Uniplant insertion, cervical mucus and sperm penetration tests were affected in 70.6% of the women. Forty-eight hours after implant insertion, the women were affected. Follicular rupture occurred in the majority of the women 48 h after implant insertion. Based on these results, it is possible to conclude that Uniplant can affect estradiol and LH preovulatory peaks and disrupt the process of cervical mucus production and sperm penetration, but it was unable to prevent ovulation when inserted in the preovulatory phase.

PIP: In Brazil, physicians inserted one single capsule of the nomegestrol acetate contraceptive implant (Uniplant) subcutaneously in the gluteal region of 17 healthy female volunteers (mean age = 24.62 years) when their cervical mucus score was 8-10. They performed cervical mucus examination, sperm penetration test, and transvaginal sonography during the control cycle and during the first cycle of Uniplant use. They took blood samples to measure estradiol, luteinizing hormone (LH), and progesterone. Uniplant contained 55 mg of nomegestrol acetate. The researchers aimed to determine the time between Uniplant insertion and changes in cervical mucus and in the ability of sperm to exhibit forward motility in the cervical mucus. When Uniplant was inserted in the early follicular phase, the preovulatory peaks of estradiol and LH were significantly lower than preinsertion peaks (539.4 vs. 1087.1 pmol/l and 12 vs. 40.4 IU/l, respectively; p 0.01). The lower progesterone levels in the treatment cycle were not significantly different than preinsertion progesterone levels (46.6 vs. 53.8 nmol/l; p = 0.055). Ultrasonography and progesterone levels indicated that 16 of the 17 treatment cycles were ovulatory. Neither cervical mucus nor sperm penetration was affected in the first 12 hours postinsertion. By 24 hours postinsertion, 70.6% of the women exhibited significant changes in both cervical mucus and sperm penetration. At the end of 48 hours, all 17 women had these changes. These findings suggest that Uniplant inserted in the periovulatory phase affects cervical mucus production, sperm penetration, and preovulatory peaks of LH and estradiol but does not affect ovulation.

Intrauterine devices: learning from the past and looking to the future.

This paper reviews the historical development of the IUD, describing the challenges and successes, and attempts to offer a balanced perspective for family planning service workers today. Modern IUDs are an important component of family planning services and an excellent contraceptive choice for properly screened women, providing contraception that is safe, effective, long lasting and cost effective. Potential research strategies for the future are also discussed.

PIP: Although there are 100 million current IUD users on a global level, unwarranted apprehension about the device's safety persists on the part of both service providers and potential acceptors. Much of this concern is based on experiences with IUDs such as the Dalkon Shield that are no longer in use and unsubstantiated assertions emerging from past IUD research (e.g., the existence of an IUD-pelvic inflammatory disease link). The development of medicated copper IUDs has renewed confidence about the effectiveness and safety of this form of contraception. The Copper T 380A, Multiload Copper-375, Nova-T, and levonorgestrel-releasing IUD are expected to be the pillars of IUD contraception for the 1990s and beyond, although high production and distribution costs are jeopardizing widespread use in developing countries. Current research is focused on reducing expulsions and medical removal rates through innovative design modifications. At this point, there is sufficient data from prospective multicenter clinical trials to enable evaluation of rare side effects. There is a need, however, to widen the scope of research activities to focus on users' needs and expectations and the impact of sociocultural context. Educational campaigns directed both at the public and the medical community would help to dispel remnants of misinformation.

FHI quinacrine studies.

PIP: Scarcity of long-term funding has influenced Family Health International (FHI) to stop new animal studies on the safety of quinacrine pellets that are used in nonsurgical female sterilizations. These studies would have lasted 8 years and cost $8 million. FHI planned to examine quinacrine's potential toxicity, including life-time carcinogenicity in rodents. In the early 1980s, it sponsored toxicology studies but the US requirements for evaluating toxicity were different then. In 1994, a meeting of experts evaluated quinacrine research and FHI then decided to conduct short-term genetic toxicity tests on quinacrine. These tests proved that quinacrine causes genetic damage in vitro. FHI sent both the World Health Organization (WHO) and the US Agency for International Development (USAID) these results. FHI is presently conducting follow-up of two clinical studies in Chile (USAID-funded) and in Vietnam (Mellon Foundation-funded). A small cancer cluster promoted the follow-up study of 1492 women in Chile. One woman had developed the rare form of uterine cancer called uterine leiomyosarcoma. Data up to 1991 reveal that quinacrine did not increase the risk of cancer, but the sample size was too small to confirm quinacrine's safety relative to cancer. The Vietnamese government asked FHI to conduct a follow-up study that includes more than 2000 quinacrine acceptors and about 1500 controls. Ministry of Health providers had inserted the quinacrine pellets in the cases. Based on the findings of the original study, WHO recommended that Vietnamese officials suspend quinacrine sterilizations until more toxicologic evaluation of quinacrine could be performed.^ieng

Clinical evaluation of the TCu 380A IUD at six Latin American centers.

Compared with other contraceptive methods such as sterilization and oral contraceptives, the prevalence of IUD use in Latin American countries is relatively low. This study evaluated the clinical performance of the TCu 380A IUD in six Latin American clinics to determine whether its performance was a determining factor in its low prevalence, and to provide efficacy and safety data based on local data sets to Latin American service providers. The 12-month unintended pregnancy rate ranged from 0.0 to 1.7 per 100 women and the 12-month discontinuation rates for all reasons, from 3.3 to 21.0 per 100 women. Statistically significant differences in discontinuation rates were observed among clinics, and could be explained, in part, by the different sociodemographic and clinical characteristics of women attending the clinics. The overall performance and acceptability of the TCu 380A IUD was considered satisfactory and comparable to those reported from other countries. Thus, the low prevalence of IUD use in Latin America is probably related to barriers to its use rather than its clinical performance.

PIP: Although the IUD is one of the most widely used contraceptive methods in the world, only 4.1% of reproductive aged married women in Latin America currently use it. Chile, Colombia, and Ecuador are among the few countries in the region where more than 10% of such women report its use. The authors report their findings from a clinical evaluation of the performance of the TCu 380A IUD at six clinic sites in Chile, Mexico, El Salvador, Peru, and Venezuela. Data were analyzed for two sites in Mexico. The study investigated whether the performance of the IUD was a determining factor in its low prevalence and provided efficacy and safety data based upon local data sets to Latin American service providers. The twelve-month unintended pregnancy rate among the 854 subjects ranged from 0.0-1.7 per 100 women, while the twelve-month discontinuation rates for all reasons ranged 3.3-21.0 per 100 women. The statistically significant differences in discontinuation rates observed among clinics may be partly explained by the different sociodemographic and clinical characteristics of women attending the clinics. Overall, the performance and acceptability of the TCu 380A IUD were found to be satisfactory and comparable to those reported from other countries. The low prevalence of IUD use in Latin America is therefore probably related to barriers to its use instead of to its clinical performance.

Pharmacokinetics of once-a-month injectable contraceptives.

The addition of a short- or medium-acting estrogen ester to the long-acting progestins depot-medroxyprogesterone acetate (DMPA) and norethisterone enanthate (NET-EN) to produce "combined" injectable formulations has proved a successful strategy in the development of once-a-month injectable contraceptives. Recent clinical pharmacokinetic studies undertaken on once-a-month injectable contraceptives in various WHO Collaborating Centers have guided the selection of the estrogen-progestogen combinations, ratios and dose schedules. At least three combined once-a-month injectable preparations exhibit acceptable pharmacokinetic and pharmacodynamic profiles; however, further improvement in the design of optimal estrogen/progestin injectables are expected during this decade.

PIP: The World Health Organization [WHO] Special Programme of Research, Development and Research Training in Human Reproduction has coordinated the developmental strategy of combined once-a-month injectable contraceptives. The strategy consists of the selection, based on pharmacokinetic data, of appropriate long-acting progestin-estrogen combinations to develop at least 2 sustained-release formulations; assessment of safety and effectiveness of these formulations in clinical research facilities; and their evaluation at field level through service facilities of national family planning programs. WHO Collaborating Centers were involved in selecting the estrogen-progestogen combinations, ratios, and dose schedules. Research has found at least 3 combined once-a-month injectable contraceptives that demonstrate acceptable pharmacokinetic and pharmacodynamic profiles. 2 safe and effective once-a-month contraceptive formulations (Cyclofem and Mesigyna) can join the existing choice of contraceptive methods. WHO expects more improvement in the design of optimal estrogen/progestin injectables in the 1990s.

Comparative study on the efficacy, acceptability, and side effects of a contraceptive pill administered by the oral and the vaginal route: an international multicenter clinical trial.

The objective of this multicenter randomized clinical trial was to compare the efficacy, acceptability, and occurrence of side effects associated with the oral versus vaginal route of administration of contraceptive pills. Eight hundred nineteen healthy, parous women of reproductive age were recruited at family planning clinics and research centers, members of the South to South Cooperation in Reproductive Health, in seven countries of the developing world. These women were randomly assigned to use either oral or vaginal administration of the same contraceptive pill, which contained 250 micrograms levonorgestrel and 50 micrograms ethinyl estradiol. No statistically significant differences were found in discontinuation rates between the two groups after 1 year. Involuntary pregnancy rates after 1 year were not statistically significantly different between the two groups. The vaginal route of administration appears to be as acceptable and efficacious as the oral route.

PIP: The objective of this multicenter randomized clinical trail was to compare the efficacy, acceptability, and occurrence of side effects associated with the oral versus vaginal route of administration of contraceptive pills. This study started in June, 1987, and data collection extended up to April, 1992, at family planning clinics and research centers, members of the South to South Cooperation in Reproductive Health, in seven countries of the developing world. The 819 subjects were from 17 to 39 years of age, had already had at least one pregnancy, had had regular menstrual cycles for 3 months before, were exposed to the risk of pregnancy, and were not using any other method of contraception. 424 were randomly assigned to use the pills orally (which contained 250 mcg levonorgestrel and 50 mcg ethinyl estradiol), whereas 395 inserted the pills vaginally. 625 subjects completed at least 6 months of use, 326 used the pills orally and 299 used the pills vaginally. 385 subjects completed 1 year of pills use, 201 in the oral group and 184 in the vaginal group. The 1-year discontinuation rate per 100 subjects per year for the oral group was 34.71 +or- 2.42, while it was 36.35 +or- 2.53 for the vaginal group. This difference was not statistically significant. The only single reason of statistically significant difference for discontinuation was "desire for pregnancy" (p = 0.444). Paired value analysis of subjects completing 12 months of study showed that women in the oral group had a statistically significant increase in weight, from a mean of 55.8 kg at admission to a mean of 56.9 kg at 6 months (p 0.05) and 57.3 kg at 1 year (p = 0.05). The mean weight of the vaginal group increased from 56.52 kg to 57.22 kg (p = 0.036) at 12 months. Significantly more complaints of vaginal discharge were recorded in women using the pills by the vaginal route (p = 0.001). However, only one subject discontinued the pills because of vaginal discharge.

[Non-surgical female sterilization using quinacrine: efficacy of two insertions of quinacrine pellets]. / Stérilisation féminine, non chirurgicale avec l'emploi de quinacrine: efficacité de deux insertions de pellets de quinacrine.

In a group of 159 women at Santiago du Chili, fertility control by means of chemical occlusion of the utero-tubular junction was assessed. Two transcervical intra-uterine insertions of 216 mg of quinacrine, carried out at an interval of one month and associated with 50 mg of intra-uterine diclofenac and 150 mg of intra-muscular diclofenac resulted in a pregnancy rate after 12 months of 2.1 per 100 women and a Pearl index of 1.63 at 27 months after the sterilization process. The complications and adverse events appear to be similar to those which occur during insertion of an IUD and were minor and transient, disappearing within a few hours or at most 2 days after the procedure.

PIP: A group of 147 women participated in a study of outpatient tubal occlusion with quinacrine pellets at a hospital in Santiago, Chile. Six pellets, each containing 36 mg of quinacrine, were inserted transcervically into the uterus by means of a plastic tube in a procedure resembling IUD insertion. The women also received 50 mg of intrauterine diclofenac and 150 mg of intramuscular diclofenac. The initial procedure was carried out within the first postmenstrual cycle week, and was repeated at the same cycle phase on month later. No procedures were done within 42 postpartum days. The study women were 34.9 years old an average and had an average of 4.9 living children. Of the 159 patients who completed the two scheduled insertions, 140 were followed for 27 months and the other 19 were lost to follow-up. Three women became pregnant within two years. The Pearl index was 1.63 for 2198 woman-months. The percentages of pregnancies were 0.62 for the first year and 1.25 for the second year. None of the pregnancies was ectopic. One pregnancy was terminated by a medical abortion, and the patient was surgically sterilized. No abnormality was observed during laparotomy. The other two pregnancies terminated in normal delivery of healthy infants. Twenty women had adverse reactions during the 24 months of observation, but most were minor. No hospitalization or additional surgical procedures were required. Three women had post-insertion metrorrhagia, which lasted a maximum of two days.

Comparative study on the efficacy and acceptability of two contraceptive pills administered by the vaginal route: an international multicenter clinical trial.

The efficacy and acceptability of two widely used oral contraceptive tablets, one containing 250 mg levonorgestrel and 50 micrograms ethinyl estradiol and the other containing 150 micrograms desogestrel and 30 micrograms ethinyl estradiol, administered by the vaginal route were compared in 1055 women studied over 12,630 woman-months of vaginal contraceptive pill use. This multicenter clinical trial was performed in nine countries of the developing world by the "South to South Cooperation in Reproductive Health," an organization founded by scientists from the Third World working in the area of reproductive health, and the study was developed and coordinated by one of these centers. The findings of this study confirm the efficacy of both these tablets when administered by the vaginal route. Involuntary pregnancy rates at 1 year of 2.78 for subjects in the levonorgestrel group and 4.54 for subjects the desogestrel group showed no statistically significant difference between the two groups. However, total discontinuation rates of 47.01 for subjects in the levonorgestrel group and 56.33 for subjects in the desogestrel group showed a statistically significant difference between the two groups, and discontinuation rates attributable to prolonged bleeding of 0.6 for subjects in the levonorgestrel group and 3.2 for subjects in the desogestrel group were also significantly higher in the group of subjects using the desogestrel vaginal contraceptive pill. Blood pressure remained at admission values throughout treatment. A statistically significant weight increase from admission values occurred in both groups of subjects.

PIP: Efficacy and acceptability of 2 combined oral contraceptive pills administered vaginally are summarized. This is the 1st collaborative trial published by the South to South Cooperation in Reproductive Health. 1055 women participated in 12,630 cycles, in 9 countries, from June 1988 to May 1991. The pills were commercially available tablets containing 50 mcg ethinyl estradiol and 250 mg levonorgestrel (Schering AG, Sao Paulo, Brazil), or 30 mcg ethinyl estradiol and 15 mcg desogestrel (Organon, Sao Paulo, Brazil). Subjects were aged 17-39 younger and of lower parity from Mexico and Dominican Republic and older from Egypt and China. All had at least 1 pregnancy. 675 participated for 6 months, 470 for 1 year, 364 for 18 months, and 210 for 2 years. The 1-year discontinuation rate averaged 47.01% for the levonorgestrel group and 56.33% for the desogestrel group (p = 0.0061); 2-year discontinuation rates were 48.01% and 69.36, respectively, explained in part by higher involuntary pregnancy rates and prolonged bleeding rates in the desogestrel group. The most common medical reasons for stopping contraception were unplanned pregnancy, vaginal or vulval irritation, nausea, vaginal discharge and headache. Vaginal irritation was reported by 1%, 9 in each group. There were 32 pregnancies, 14 in the levonorgestrel and 18 in the desogestrel group. 17 were in missed pill cycles and the rest were method failures, 6 in the levonorgestrel group and 9 in the desogestrel group. The Pearl index varied from 0 in Nigeria to 12.24 in Mexico, and was 2.45 for levonorgestrel vs. 3.74 for desogestrel. There was a wide variation in discontinuation rates by center: Brazil and China had few, while many women from Dominican Republic, Mexico and Zambia left the study. Bleeding problems were common complaints, more so in the desogestrel group. There were 363 women with intermenstrual bleeding (only once in 80%), 148 with spotting (only twice in 65%). Bleeding duration was significantly less in pill cycles than baseline, pressure. Women gained an average of 1 kg over 2 years, more in the desogestrel group. The pregnancy rate of 2.78 is within the range reported for levonorgestrel rings.

Recommendations of the International Symposium on Contraceptive Research and Development for the Year 2000 and Beyond.

PIP: The government of Mexico and the UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development, and Research Training in Human Reproduction organized an international symposium on "Contraceptive Research and Development for the Year 2000 and Beyond" that was held March 8-10, 1993 in Mexico City. 11 recommendations were established: 1) reproductive and sexual health should be given priority in both governmental and nongovernmental health research agendas, with coordination and collaboration between public and private sectors, nationally and internationally; 2) more funds should be provided by international donors for such research in developing countries; 3) women's health advocates and potential users should be represented on advisory bodies and in the decision making processes; 4) the existing health infrastructure and family planning services available, method potential, and safeguards concerning safety, effectiveness, and consent should be considered before adopting a new procedure; 5) "basic biomedical, technological, clinical, epidemiological, and social science research" leading to new or improved methods that are safe, effective, affordable, suitable for different age groups and designed in response to user's needs should receive increased support; 6) support should also be increased for "introductory, sociocultural, programmatic, operational, epidemiological, and qualitative research" that improves information, method, or service delivery; 7) research is needed on sexuality, gender roles, and gender relationships in different cultures; in particular, on discrimination and violence against women, sexual behavior, risk taking attitudes toward disease transmission and pregnancy, men's perceived needs, and the reasons for refusal of or inability to use services available; 8) industry, especially in developing countries, should collaborate with national regulatory agencies in order to expedite the process of development; 9) research should be undertaken that ensures quality abortion services that are safe, affordable, and accessible; 10) special attention should be given to the needs of adolescents; and 11) research findings should be disseminated to policy and opinion makers, providers and users of methods, and the general public and applied to problem solving.^ieng

Inactivation of SH groups with sesquiterpene lactones: effects on nuclear decondensation pattern / motility induced by heparin in human spermatozoa.

PIP: In Guadalajara and Mexico City, Mexico, researchers collected and analyzed semen samples from fertile men who were sexually abstinent for 3 days to evaluate the effect heparin has on sperm nuclear decondensation patterns and motility. They used 3 sesquiterpene-lactones to inactivate the thiol groups on the outer membrane of sperm cells: I (17, 18 dehydroviguiepinin), II (Budlein A), and III (Zaluzanin A). Sesquiterpene-lactones I, II, an III had an inhibitory effect of 81%, 73%, and 27%, respectively, 6 hours after the sperm had been incubated with heparin for 6 hours. First mixing the sperm with reduced glutathione before adding 17, 18 dehydroviguiepinin increased the decondensating effect of heparin 350% above that of sperm not incubated with both glutathione and heparin. Sperm motility fell 80%, 60%, and 16%, respectively, 15 minutes after incubation with sesquiterpene-lactones I, II, and III. When sperm was incubated with heparin only, sperm motility was consistently higher for 5 hours. None of the compounds used to incubate the sperm affected sperm viability. The findings provided more information about the molecular biology of mammalian spermatozoa and suggested that sesquiterpene-lactones may be effective male contraceptives.^ieng

Steroid research at Syntex: "the pill" and cortisone.

The period from late 1949 through 1951 was an extraordinarily productive one in steroid chemistry and especially so at Syntex S.A. in Mexico City. Two of the most important Syntex contributions--the synthesis of 19-nor-17 alpha-ethynyltestosterone (norethindrone) and of cortisone from diosgenin--are described from a historical perspective.

PIP: The pharmaceutical industry contributed more to the published record of steroid research during the 1950s than any industry has ever contributed before to any chemical subdiscipline. Syntex, a research-oriented company in Mexico city, contributed much of the publication of industrial research of steroids. Dr. Djerassi arrived at Syntex in 1949 as associate director of chemical research. He conducted partial aromatization studies leading him to the 1st synthesis of an oral contraceptive (OC) on October 15, 1951. This steroid was 19-nor-17 alpha-ethynyltestosterone, later called norethistrone or norethindrone. Syntex submitted the product to a commercial laboratory in Madison, Wisconsin, for biological evaluation. It was indeed the most active, orally effective progestational hormone at the time. Syntex applied for a patent in November 1951. In November 1954, clinical results of norethindrone used to treat various menstrual disorders and fertility problems was presented. G.D. Searle & Co. filed for a patent for the synthesis of the double bond isomer 13 of norethindrone called norethynodrel in August 1953. Acid or human gastric juice converts norethynodrel into norethindrone. Had it not been for Searle using norethindrone in its antimotion sickness drug, Dramamine, Syntex would have filed suit against Searle. Syntex sponsored contraceptive trials with norethindrone. Various incidents prevented Syntex from obtaining US Food and Drug Administration approval to use norethindrone for contraceptive indications before Searle obtained approval to use norethynodrel. By 1964, 3 companies including Syntex were marketing 2 mg doses of Syntex's norethindrone, the most widely used active ingredient in OCs. Dr. Djerassi also played a key role in the synthesis of cortisone from diosgenin, a chemical derived from Mexican yams. This synthesis was a more economical industrial route to cortisone than previous routes.

A bright future for IUDS: new technology and research trigger expanded interest.

PIP: Refuting research findings on IUDs from the early 1980s, and controversy over the safety of the Dalkon Shield, research published over the past 10 years indicates that modern IUDs are safe and effective for most women. Better understanding of pelvic inflammatory disease (PID) reveals PID to present no more frequently among IUD user selection, insertion, and monitoring techniques are followed. Following such guidelines, and avoiding use in women at high risk for infection from sexually transmitted diseases (STD) will generally provide effective, acceptable, and inexpensive protection against pregnancy. The TCu 380 A IUD has in fact proved to be as effective as injectables or newly- developed hormonal implants. Accordingly, expanded use around the world is encouraged. The IUD has already become the most widely used from of reversible contraceptive with 85 million users in China, developed nations, Indonesia, Mexico, Egypt, and India. China claims 60/85 million users. Family Health International clinical trials involving 10,000 women in 23 developing countries during the period 1985-89, found declining removals due to complications, with increasing rates of method continuation. Women having a baby are ideal candidates for IUD acceptance and insertion. Such women may receive IUD insertion 10 minutes following expulsion of the placenta, while not posing risks to safe breastfeeding. Method drawbacks include the need for trained health professionals in insertion, removal, and follow-up exams over the 1st 3 months following insertion. IUDs also do not protect against STDs.^ieng

Researchers assess data on long-term safety of non-surgical sterilization method.

PIP: Concerned over a possible link to cancer, researchers from Family Health International (FHI) have begun investigating the long-term safety of the chemical used for non-surgical sterilization, a study being carried out among Chilean women. In the late 1960s, the chemical quinacrine hydrochloride was found to be an effective means of occluding the Fallopian tubes for the purpose of contraceptive sterilization. This is done through the transcervical insertion of 2 quinacrine pellets, which inserted 1 month apart. The use of quinacrine has several advantages over surgical sterilization: no incision, general anesthesia, or hospitalization is required; it can be performed by paramedics on an outpatient basis; and it effectively prevents pregnancy. Quinacrine, however, also has disadvantages, including the fact that it requires 2 applications, that the sterilization cannot be reversed, and that it increases the risk of ectopic pregnancy. Additionally, the long-term safety of this contraceptive method is not yet known. From the late 1970s to 1986, 572 women in Chile took part in clinical trials of quinacrine, tests which were supported by FHI. Continuing to monitor the health of these women, FHI recently discovered 8 cases of malignancy in 6 different anatomical sites. Although it is not known whether this figures reflect a significant difference in the incidence of malignancies between the trial group and the general population, the finding has prompted the organization to undertake a study of a possible association between the use of quinacrine pellets and malignancy.^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.

Ethics and the reproductive process.

Changes in reproductive technology and contraceptive availability have resulted in ethical reconsiderations in many countries. The United States has been no exception. A discussion of the applicable ethical principles for contraceptive research and family planning programs is presented. Each country must decide its own individual response to a given ethical problem. The paper does not propose solutions but is designed to raise the necessary questions.

PIP: Contraceptive availability and reproductive technology both represent new considerations in the ethical structures in many countries. In both developed and developing countries, debates, political protests, and court battles are being conducted as each country attempts to integrate these issues of reproductive control into their respective ethical systems. There are many ethical considerations that must be made in terms of contraceptive research and family planning programs. The UN has integrated into their policy the concept of reproductive freedom for all couples as a moral right. But what should the limitations of the right be? Things to consider are: transmission of disease to offspring, resistance to prenatal care, lack of child rearing ability, psychological child abuse, overpopulation, non-marriage i.e. singles and homosexuals. Also, who should determine these limitations? People to consider include the woman, the couple, physicians, counselors, professional groups, the clinic, ethical committees, the legislature, religious groups, or the media. Which of these groups actually make the decisions and who should make these decisions are also important questions. In terms of contraceptive research, the issue of informed consent must be considered in light of the varying cultures of the world. In the US informed consent is based on the Belmont Report which came from Congress and establishes that informed consent must be given before any medical research is allowed. Further the consent must not be coerced by intimidation or financial incentive. In terms of family planning services the ethical considerations include: attitudes of providers, attitudes of government, financial availability, role models and cultural taboos, the role of the woman, the role of the husband. Finally the AIDS epidemic adds an additional ethical aspect. Should methods be used that don't protect against AIDS?