The return of the pharmaceutical industry to the market of contraception.

In the 1980s and 1990s, the litigious climate in the US had a catastrophic effect on sales of many major contraceptives. Although oral contraceptives escaped controversy, the intrauterine device (IUD) and Norplant(R) were two targets of damaging litigation. The IUD was withdrawn from the market in 1985. Since 1994 when the attacks began against Norplant, its US sales have dramatically declined, even though no fault has been found in the method or its development. In general, pharmaceutical companies were extremely hesitant to develop new contraceptives during this period. The bleak outlook, however, began to shift in the late 1990s, as fertility rates began to decrease worldwide and contraceptive users increased. By 2025, 2500 million women will comprise the customer base for contraception. Global pharmaceutical companies are now participating in expanding markets overseas and have launched and continue to develop a range of new long-term reversible, and highly effective, contraceptive products outside the traditional oral contraceptive field. Two new contraceptives on the way to the US market are: Mirena, a levonorgestrel-releasing intrauterine system manufactured by Schering-Leiras; and Implanon, a single implant system manufactured by Organon of the Netherlands. Other birth control methods soon to be launched include: emergency contraceptives, the contraceptive patch, monthly contraceptive injections, mifepristone for medical abortion, and modified oral contraceptives.

The cost of the menstrual cycle in young Swedish women.

The purpose of this study was to evaluate the cost of the menstrual cycle for young Swedish women aged 14-20 years. The young women were randomly selected and interviewed by a trained female psychologist; a total of 68 young women completed the interviews. Twenty of the girls used oral contraceptives, while 48 had natural periods. The oral contraceptive users had a lighter menstrual flow and shorter periods (1 day less) than the girls with natural menstruation. The oral contraceptive users experienced less menstrual pain, used fewer painkillers and did not stay at home during their periods as often as the girls with natural periods. The cost of sanitary protection products was about US$1 per month less for the oral contraceptive users. Girls taking oral contraceptives also avoided stained underwear and soiled bedlinen significantly more often than the non-oral contraceptive users. The study design did not allow for cost estimates on soiled underwear, bedlinen or lost work- or schooldays. The results of the study indicate that expenditures related to the menstrual cycle are considerable for young Swedish women.

A detailed analysis of menstrual blood loss in women using Norplant and Nestorone progestogen-only contraceptive implants or vaginal rings.

Changes to the pattern of menstrual bleeding are almost universal in women using progestogen-only methods of contraception, and are an important cause of discontinuation of these methods. The present study was designed to explore the changes in menstrual bleeding patterns and objectively measure menstrual blood loss (MBL) in 110 women before and during one year of use of 4 different progestogen-only contraceptives: Norplant subdermal levonorgestrel implants; Nestorone progestogen 4-cm or 6-cm implants nominally delivering 100 microg or 150 microg daily; or a vaginal ring (CVR) delivering 100 microg of Nestorone (NES) daily (CVR users were limited to only 6 months of use). Groups could not be directly compared because of the differences in numbers of subjects and durations of treatment. The total MBL during each of the three 8-week collection periods during treatment decreased significantly in each group compared to the total blood loss in the two control cycles (greater than 50% decrease in all groups during the first 6 months), although the differences between individual women at the extremes remained considerable. The highest blood loss measured on any single day during the treatment collection periods was significantly reduced (p <0.001) in users of all four devices in all three collection periods compared to the control period (CVR users did not have a 3rd collection period). The Nestorone-releasing CVR was associated with an 88% reduction in mean MBL and a high incidence of amenorrhea at 6 months. There was considerable variation in percentage reduction in total blood loss at 6 and 12 months between individual women ranging from 100% (women with amenorrhea) to a small minority experiencing an increase compared with control cycles. The increases in measured blood loss during treatment were almost entirely in women with light bleeding in the control period and were related to prolonged episodes of light bleeding rather than heavy bleeding. Women contemplating use of a progestogen-only contraceptive method need to be counseled about alterations to the menstrual cycle but can be reassured that total blood loss will usually be much less than with normal cycles.

Contraceptive strategies for young women in the 21st century.

Safe, effective and affordable contraceptives have been available for a few decades, yet, in many countries, the struggle for reproductive rights continues. Children, still, are forced to give birth to children in many nations. In most industrialized countries, where contraceptive counselling and abortions have been options, fertility rates have reached all time lows. Effective contraception improves health and well-being as well and may be used for conditions other than birth control. Young girls often initially take oral contraceptives primarily to reduce menstrual pain and blood loss; they also welcome a contraceptive that eliminates menstrual bleeding. Women using oral contraceptives and Norplant experience about 50% reduction in menstrual blood; 90% reduction in blood loss is achieved with the levonorgestrel intrauterine system (Mirena). Teenagers and their parents are often misinformed about the side-effects of oral contraceptives and birth control in general, which may adversely affect compliance. Adequate, user-friendly and supportive information about contraception is necessary to ensure proper use of the pill and other birth control methods. In addition, emergency contraceptives should be easily accessible. The mortality and morbidity of young women would be dramatically reduced by the global use of medical abortion as well. Only a combined effort by policy makers, educators, parents and health-care providers can enhance the reproductive (and future!) health of both young females and males.

Pushing the frontiers of science--the Population Council's Microbicide Basic Science Network on vaginal microbicide research.

Microbicides are the new frontier of products for the prevention of sexually transmitted infections (STIs). Twelve years ago, scientists realized that existing spermicides had some anti-microbial activity and perhaps could be improved or reformulated with new compounds to provide a complete barrier against STIs. However, the development and successful marketing of an effective, non-toxic, convenient and affordable vaginal microbicide that women can use on a long-term basis hinges on a close collaboration between research institutions and the pharmaceutical industry. The Population Council has recently taken the first step in instituting a multifaceted strategy for the development of a microbicide by establishing the Microbicide Basic Science Network, comprising of scientists with diverse backgrounds and expertize.

Female contraception: changing priorities.

PIP: Late marriage, withdrawal, and induced abortion were the methods that achieved the demographic transition from high to low birth and death rates in Europe and North America. The demographic transition in France was early and significant, possibly because it was the most populous country in Europe. Induced abortion caused high morbidity and mortality, especially among working-class women. In countries where abortions are still illegal, women die, mainly due to bleeding and infections. Women who survive often suffer infertility. Modern surgical techniques and the availability of hormonal interruption of early pregnancy make abortions safe. Today, Europe has very low fertility. In Europe, Ireland has the highest total fertility rate (TFR) (2.1) followed by Sweden (2). All the other European countries have TFRs much less than 2 (1.3-1.8). The populations of these countries will decline if massive immigration does not occur. Very effective contraceptives have contributed to this low fertility. Women in Europe use contraceptives during most of their reproductive years. Thus, contraceptive safety and efficacy are extremely important. Another important consideration is the effect of contraceptives on sexually transmitted diseases. A very rapid fall in death rates has occurred in developing countries without a concomitant fall in birth rates, resulting in very high population growth. Safe and effective contraceptive methods and the revolution in information technology exist today but did not when Europe and North America went through their demographic transition. These 2 conditions may help speed up the demographic transition in developing countries. Many developing countries must reevaluate their priorities to achieve safe motherhood and a subsequent reduction in fertility. Many African governments spend more money on the safety of their Heads of State than on maternal health. Improvements in contraceptive counseling, distribution, and promotion are needed to bring about fertility reduction in developing countries.^ieng

Ovarian function during use of a levonorgestrel-releasing IUD.

Ovarian function was studied for two complete menstrual cycles in 9 regularly menstruating women and for 8 weeks in three amenorrhoeic women who had used levonorgestrel-releasing IUDs (LNG-IUD) for more than four years. Nine patients using copper IUDs (Nova-T) were studied for two complete menstrual cycles as controls. According to progesterone levels, 15/17 cycles in women using LNG-IUDs were ovulatory, whereas only 8/17 cycles showed normal follicular growth and rupture as judged by ultrasound. In ovulatory cycles, the peak progesterone levels were lower than in the controls. The preovulatory estradiol and LH peak levels were also lower than in control subjects. SHBG levels were lower in LNG-IUD users than in copper IUD users. It is concluded that, although the dose of levonorgestrel released from the IUD is very low, it probably exerts an effect on the gonadotrophin secretion, which disturbs follicular development in many of the women studied, which in addition to the local effect on the endometrium, contributes to its high contraceptive efficacy.

Clearance of levonorgestrel from the circulation following removal of NORPLANT subdermal implants.

The disappearance of levonorgestrel from plasma after the removal of NORPLANT subdermal implants was studied in 12 women who had been treated from 5.5 to 78 months. The existence of one or two half-lives for the rate of disappearance was assessed. The influence of body weight, body fat and length of treatment upon levonorgestrel clearance was studied through stepwise regression analysis. It was found that the levonorgestrel decay rate after implant removal can be entirely accounted assuming one half-life of 42 +/- 16 h (mean +/- SD; range 13 to 62 h). Stepwise regression analysis showed that levonorgestrel half-life is positively correlated with body weight and not significantly correlated with the length of treatment or body fat. It is concluded that, after long-term administration of levonorgestrel via subdermal implants, the major part of the steroid is cleared from plasma within 96 h and that only trace amounts are detected in the following days.

Effect of sulfasalazine and its analogs on fertility in male rats.

Several derivatives of sulfasalazine were tested for their antifertility activity in male rats. The compounds were administered to groups of rats daily by oral gavage for 28 days. Fertility of the rats treated with sulfasalazine or compound CH 74A was reduced, while other compounds had no effect. In a subsequent experiment, therefore, only the active compounds were studied further. Fertility of rats treated with sulfasalazine, compound CH 74A, CH 99A or sulfapyridine was reduced during 40 days of treatment. At the end of treatment, body weights were reduced in higher dose groups of sulfasalazine, CH 74A and sulfapyridine compared to control animals. The weights of the testes, prostate or seminal vesicle were not altered by any of the treatments. On the other hand, weight of the epididymides decreased in all higher dose groups except in CH 99A-treated animals. Sperm motility decreased in all the treated rats except in animals treated with low dose of sulfapyridine, whereas epididymal sperm count decreased in all but CH 99A-treated animals. These results suggest that sulfasalazine and its derivatives bring about their antifertility effects by decreasing sperm motility and/or number of spermatozoa.

Contraception with NORPLANT implants and NORPLANT-2 implants (two covered rods). Results from a comparative clinical study in Sweden.

Two-hundred-and-forty healthy women, ages 18 to 40 years, were randomized in a ratio of 2:5 to use NORPLANT implants or NORPLANT-2 implants. Through three years of use, no pregnancies were recorded among women using NORPLANT implants and two pregnancies were noted among women using NORPLANT-2 implants resulting in a cumulative net pregnancy rate of 1.3 +/- 0.9 per 100 acceptors (mean +/- SE) by the end of year three. This difference was not statistically significant. During the fourth year, no pregnancies were observed in the NORPLANT group, but 4 pregnancies occurred in the NORPLANT-2 group. The most common reason for terminating the study was bleeding disturbances. During the first year there were significantly more terminations due to bleeding problems in the NORPLANT group than in the NORPLANT-2 group. However, during the second year of use the proportion of women discontinuing for bleeding problems dropped considerably among NORPLANT users and during the third year very few women in either group discontinued because of bleeding problems. The continuation rates after one year were for NORPLANT users 59.4% and for NORPLANT-2 users 77.2%. Corresponding figures after three years of use were 46.1% and 51.7%, respectively. The second most common reason for discontinuation was depression and other mood changes. In both groups we noted a slight increase in weight during the study and a slight decrease in blood pressure and hemoglobin levels with time. In conclusion, both NORPLANT and NORPLANT-2 implants are very effective methods for contraception. The efficacy of NORPLANT-2 implants, however, was not acceptable during the fourth year of use in this study. The latter system could, however, become a suitable three-year contraceptive method, possibly with less bleeding disturbances than NORPLANT in the first year.

Long-term follow-up of women treated with Norplant implants.

This report describes the long-term follow-up of 376 women who received NORPLANT implants in the period October 1974 through May 1979. One-hundred-and-ten subjects received replacement implants after variable lengths of use of the first set. The average levonorgestrel plasma levels declined steadily through eight years of use of NORPLANT capsules (r = -.937). Values were 0.35 ng/ml, 0.29 ng/ml and 0.22 ng/ml at treatment years 1, 5 and 8, respectively. Levonorgestrel plasma levels after replacement with a second set of implants were similar to those observed after the first insertion, either when placed in the same site as the first set or in a different area. Nineteen pregnancies occurred during 18,530 woman-months of use of the first set of implants, eleven of them during years 6 through 8 of treatment. The Pearl Index for the first 5 years of NORPLANT implants use was 0.63. No pregnancy has occurred in 4194 woman-months observed during treatment with a second set of capsules. Fifty-six women (14.9%) out of 376 acceptors of the first implant and 10 (9.1%) out of 110 acceptors of the replacement implants were terminated for other medical reasons, mainly bleeding problems and side effects commonly associated with hormonal contraception. Two women died while using NORPLANT implants, one of a cardiac arrest after surgery for a gallbladder disease and one because of endocranial hypertension originating from the rupture of an aneurism of the median cerebral artery. The bleeding pattern observed in the three months after NORPLANT capsules replacement was similar to that observed in the 90 days before replacement and different from that experienced by the same women in the first 90 days of implant use. This finding can be interpreted as an indicator of adaptive changes experienced by the target organs during long-term continuous administration of levonorgestrel. The prompt recovery of fertility after removal of NORPLANT implants suggests that these changes are reversible.

Plasma levels of levonorgestrel and free levonorgestrel index in women using NORPLANT implants or two covered rods (NORPLANT-2).

Plasma levels of levonorgestrel, sex hormone binding globulin (SHBG) and estradiol were studied during four years in 283 healthy women using either NORPLANT implants or two covered rods (NORPLANT-2). The women were randomized to use either type of implant. Both implant systems have previously been shown to have similar release rates of levonorgestrel. In both groups plasma levels of levonorgestrel decreased throughout the study, and there were no statistically significant differences between the two groups in mean plasma levels of levonorgestrel. During the study 8 women became pregnant. All pregnancies but one occurred after 35 months of implant use and only in women using the covered rods. No significant differences were seen between the women who became pregnant and the rest of the group using two covered rods with respect to plasma levels of levonorgestrel. SHBG capacity tended to be somewhat higher in women using the two covered rods. As levonorgestrel is to a great extent bound to SHBG, and in that form not biologically active, a "free levonorgestrel index" was calculated as a ratio between levonorgestrel and SHBG. This index was significantly lower in users of two covered rods than in users of NORPLANT implants at 1, 12 and 48 months of use. Women who became pregnant had significantly lower "free levonorgestrel index" than had the rest of the group. It is postulated that the difference in "free levonorgestrel index" between users of the two implant systems reflect differences in release rate, the covered rods having a lower release rate of levonorgestrel than NORPLANT throughout the observation period. It is concluded that "free levonorgestrel index" is a better parameter than levonorgestrel plasma levels to describe implant function, and to discriminate women who are at risk of pregnancy.

PIP: The plasma levels of levonorgestrel, sex hormone binding globulin (SHBG), and estradiol were compared over a 4-year period in 283 users of 2 types of Norplant systems--implants and covered rods. Plasma levels of norgestrel decreased throughout the study period in both groups, and there were no significant differences in mean plasma levels of levonorgestrel. 7 of the 8 pregnancies recorded during the study occurred after 35 months of implant use, and all involved women in the covered rods group. No significant differences were found between the women who became pregnant and the rest of the study subjects in terms of plasma levels of levonorgestrel. SHBG capacity was slightly higher in women using the 2 covered rods. The free levonorgestrel index, calculated as a ratio between levonorgestrel and SHBG, was significantly lower in users of 2 covered rods than in users of implant capsules at 1, 12, and 48 months of use. In addition, women who became pregnant had a significantly lower free levonorgestrel index. These findings suggest that the 2 covered rods had a lower release rate of levonorgestrel than Norplant implants, despite almost identical plasma levels. Thus, the free levonorgestrel index is considered a better parameter than levonorgestrel plasma concentrations to describe implant function and to predict the risk of pregnancy.

Serum estrogens and androgens in women with endometrial carcinoma.

Fifty-two postmenopausal women with newly diagnosed endometrial carcinoma and 58 postmenopausal age-matched controls were studied concerning serum levels of estrone, total estrone, estradiol, androstenedione, testosterone, dehydroepiandrosterone and its sulphate, sex steroid hormone binding globulin, follicle stimulating hormone, and luteinizing hormone. The patients had a higher mean serum level of estradiol (P = 0.006) and a lower level of follicle stimulating hormone (P = 0.001) than the controls and the significant differences remained after the number of years since the menopause and body index had been taken into account. As the serum levels of steroid hormone binding globulin tended to be lower among patients than among controls (P = 0.084), the difference in the biological effect of estradiol between the two groups was probably greater than the difference in serum concentrations would indicate. No significant difference in the ratio of estrone to androstenedione or in the mean serum level of androstenedione was found between patients and controls. These data support the role of estrogen in the etiology of endometrial carcinoma.

Medroxyprogesterone acetate pharmacokinetics following oral high-dose administration in humans: a bioavailability evaluation of a new MPA tablet formulation.

The pharmacokinetics of medroxyprogesterone acetate (MPA) in healthy female volunteers have been investigated following oral administration of single doses of six different high-dose MPA tablet formulations. Blood samples were obtained over 96 hrs following administration. The plasma was separated and analyzed in duplicate for MPA by radioimmunoassay (RIA) after extraction with petroleum ether. A two compartment open model with first order absorption was computer-fitted to the plasma concentration of MPA. Following oral administration MPA is rapidly transferred from the gastrointestinal tract to the blood circulation with a half-life of the absorption process of 15-30 min. The peak plasma concentration is reached 1-3 hrs after administration, and the biological half-life of MPA is 40-60 hrs. Following administration of 1000 mg MPA the areas under the plasma concentration-time curves (AUC 0-infinity) were calculated to (mean and S.E.): 3357 (438) nmol/l and 2403 (245) nmol/l for Leo formulation A and Farlutal, respectively (P less than 0.02). Following administration of 500 mg the areas were: 2325 (389) nmol/l, 1793 (312) nmol/l, 1778 (239) nmol/l, 1178 (209) nmol/l, and 556 (89) nmol/l for Gestapuran, Leo formulation A (P = n.s.), Leo formulation B (P = n.s.), Provera (P less than 0.001), and Lutopolar (P less than 0.001), respectively. The in vitro dissolution rates of MPA from the tablet formulations were determined and compared with the results of the bioavailability studies, indicating that a rapid dissolution rate as well as the particle size of MPA are two important factors to ensure optimal absorption of MPA from the gastrointestinal tract.

Bleeding pattern, outcome of accidental pregnancies and levonorgestrel plasma levels associated with method failure in Norplant implants users.

The aim of this study was to characterize the bleeding pattern, the outcome of pregnancies and the levonorgestrel plasma levels associated with method failures in Norplant implants users. Nineteen pregnancies are reported in 458 woman and 21,589 woman-months observed during the first eight years of Norplant use. Pregnancy rates increased slightly during the first six years of use, attaining a Pearl Index above three thereafter. All women who became pregnant had experienced a regular bleeding pattern in the six months preceding conception. Levonorgestrel plasma levels observed at different intervals before conception and during the conceptional cycle were similar to those observed in non-pregnant women at comparable intervals after Norplant insertion. The nineteen pregnancies ended in thirteen term deliveries, one premature delivery, three abortions and two ectopic pregnancies. No abnormalities were found in the infants. The two ectopic pregnancies are the only ones reported for Norplant users in The Population Council studies. The overall incidence is less than 0.8 per 1000 woman-years.

Effects of Epostane on progesterone synthesis in early human pregnancy.

Healthy women requiring abortion in early normal pregnancy were recruited to study the abortifacient effects of different doses of Epostane, an inhibitor of 3 beta-hydroxy steroid dehydrogenase, that previously has been shown to interfere with progesterone production in the luteal phase of humans and to have abortifacient effects in animals. A single dose of 100 mg resulted in decreasing progesterone and estradiol, which rapidly recovered, and none of the women started to bleed. Repeated doses of 50 or 100 mg during one day resulted in a more pronounced decrease in both progesterone and estradiol, but no bleeding. When treatment was prolonged over several days with 100 mg X 4 for five days and 400 mg X 2 for four days, respectively, a suppression of progesterone and estradiol was found and two out of four and eight out of ten women started to bleed and subsequently aborted. The treatment was well tolerated by most of the women. Routine laboratory parameters remained unaltered throughout treatment. Cortisol levels remained within the normal range.

The risk of endometrial neoplasia and treatment with estrogens and estrogen-progestogen combinations. First results of a cohort study after one to four completed years of observation.

This prescription-based cohort investigation was undertaken in order to study whether climacteric estrogen treatment of women in a Swedish population might be associated with an increased risk of endometrial cancer, and whether added progestogens can afford any protection from developing estrogen-related endometrial neoplasia. Some 23 000 women who had been prescribed estrogens were followed up regarding the outcome of neoplastic lesions of the endometrium. The results are based on an observation period of one to four completed years, corresponding to 89 000 person-years. Among those cohort members exposed to estrogens alone, regardless of the duration, the relative risk of endometrial cancer was 1.3 (95% confidence interval 0.9 to 1.7). The inclusion of premalignant endometrial changes resulted in a significantly increased relative risk of 1.6 (1.2-2.1). The relative risk estimates in association with estrogen-progestogen combinations were 0.6 (0.2-1.4) for endometrial cancer and 0.8 (0.4-1.5) when including premalignant lesions. These data indicated a possible protective effect of progestogens against the development of endometrial neoplasia. It was concluded that estrogens were - within an observation period of 4 years - associated with an increased risk of premalignant endometrial lesions.

Menstruation span--a time-limited risk factor for endometrial carcinoma.

A case-control study was undertaken to investigate the influence of reproductive factors on the risk of developing endometrial carcinoma. The study comprised 254 women with newly diagnosed endometrial carcinoma, resident in a defined geographical area, and 254 age-matched population controls. Nulliparity and late menopause were positively associated with endometrial carcinoma. Each additional full-term pregnancy resulted in a decrease in the risk by 16%. The importance of parity and menopausal age decreased with increasing life span, and in women older than 69 years these two variables did not discriminate significantly between cases and controls. The calculated number of years of menstruation (the "menstruation span") was used as a combined measure of the impact of parity, age at menarche and age at menopause on the risk of developing endometrial carcinoma. The patients had a significantly longer mean menstruation span than the controls (33.6 versus 31.2 years; p less than 0.001) and a longer span than 39 years gave a 4.2 times higher risk than one shorter than 25 years. It is suggested that the total length of time for which a woman is exposed to unopposed estrogen is important and that the effect of this hormonal influence is time-limited.