OBJECTIVE

To assess the efficacy, safety, and acceptability of NORPLANT implants when used by Chinese women.

METHODS

In a prospective, multicenter clinical trial, 10,718 women selecting NORPLANT implants were monitored semiannually for the first 2 study years and then annually through 5 years. Life table rates of pregnancy and other terminations were calculated, as were incidence rates of serious conditions leading to termination.

RESULTS

The 5-year average annual pregnancy rate was 0.3 per 100 and the ectopic pregnancy rate was minimal, 0.09 per 1000 woman-years. Pregnancy rates correlated significantly with weight, but regardless of weight group, annual average pregnancy rates were less than one per 100. Younger women experienced higher pregnancy rates than did older users. Headache, myoma, dizziness, and weight gain led more frequently to termination than did other adverse events apart from menstrual disturbances. Mortality during use was 2.0 per 10,000 years, based on 44,954 years of experience. There were no cardiovascular or cerebrovascular deaths, and no deaths were attributable to NORPLANT use. Seventy-two per 100 initial acceptors used the implants continuously for 5 years.

CONCLUSIONS

NORPLANT implants proved highly effective, safe, and acceptable among Chinese women regardless of province, age, or weight at admission.

BACKGROUND

Thrombotic thrombocytopenic purpura (TTP) is a rare, potentially fatal disease of uncertain etiology. Early diagnosis and treatment are essential to patient survival. The ]purpose of this report is to describe three patients with levonorgestrel implants (Norplant system) who developed TTP.

METHODS

A 24-year-old woman with levonorgestrel implants in place for 7 months was admitted to our hospital for treatment of TTP. Clinical symptoms included easy bruising, menorrhagia, headaches, and fever; laboratory evaluation revealed thrombocytopenia (18 x 10(9)/L) and microangiopathic hemolytic anemia. She was treated with plasmapheresis, and the implants were removed. Through the Freedom of Information Act, we reviewed all adverse events associated with Norplant use reported to the Food and Drug Administration (FDA) as of the end of 1992. Two additional cases were identified.

CONCLUSIONS

Although a causal relationship between progestogen-only contraceptives and TTP is not established by the data presented, these three cases may represent an increased incidence of TTP in women using levonorgestrel implants. Patients who receive Norplant should be advised to seek medical attention if symptoms appear. Physicians and other health care providers should be aware of the possible association between use of the Norplant system and TTP and are urged to report similar cases to the FDA.

Recent evidence points towards a substantial disturbance of the process of angiogenesis within the endometrium in women who are exposed continuously to low dose contraceptive progestogens. This results in the patchy appearance of abnormally small and abnormally large, thin-walled vessels in the superficial regions of exposed endometrium. Three-dimensional pictures were developed from digitised images of serial tissue sections of endometrium in which microvascular endothelial cells were labelled with antibodies to the endothelial cell surface antigen, CD34 and their basement membranes labelled with anti-Collagen IV antibodies. Microvessels from endometrium exposed to continuous low-dose levonorgestrel from a subdermal implant system (Norplant) displayed considerable variations in size and shape. No spiral arterioles were identified. Some microvessels showed considerable dilatation, distortion and variability in the presence of surrounding basement membrane components. Other endothelial structures included narrow, solid cords of endothelial cells, without basement membranes, which often connected with normal or abnormal vessels containing lumens. Some areas, especially deeper in the tissue, contained microvessels of normal size and shape surrounded by basement membrane. These images have revealed an overall picture of great variability in superficial endometrial vascular structures in some women using a low-dose levonorgestrel implant system which appears substantially different from that seen in normal endometrium.

OBJECTIVE

To describe serious adverse events in Norplant users from reports submitted to the Food and Drug Administration's (FDA) MedWatch Spontaneous Reporting System.

METHODS

Reports of certain serious adverse events in Norplant users in the United States from February 1991 to December 1993 were reviewed and analyzed.

RESULTS

From the introduction of Norplant in the United States in February 1991 to December 1993, the FDA received reports of 24 women hospitalized for infections at the insertion site, 14 hospitalized or disabled because of difficulties removing the capsules, 14 hospitalized for stroke, three for thrombotic thrombocytopenia purpura, six for thrombocytopenia, and 39 for pseudotumor cerebri. The comparison of reported rates with expected rates and the relationship of some of these disorders with oral contraceptives raises the suspicion of a causal association with Norplant.

CONCLUSIONS

The FDA has received reports of hospitalization or disability for infections, capsule removal difficulties, stroke, thrombotic thrombocytopenia purpura, thrombocytopenia, and pseudotumor cerebri in Norplant users. Health care professionals need to be trained in Norplant insertion and removal to ensure the proper technique. Studies are needed to determine if stroke, thrombocytopenia, and pseudotumor cerebri are causally related to Norplant use.

Deeply inserted, nonpalpable contraceptive implants can often be removed easily using 6-8 cm3 of 1% lidocaine and a single 1 cm incision. There is no need for suturing of the incision. The location of nonpalpable implants not retrieved by this procedure can be determined by a plain, soft tissue x-ray (standard AP and lateral and internal oblique; 45-55 kVP) of the area where the implants are inserted. Removal can then be accomplished several weeks later.

During the 21-month period between August 1, 1991, and April 30, 1993, 2,358 women received Norplant system insertions in either Parkland Memorial Hospital or the Dallas Maternal Health and Family Planning clinics. Forty-three percent of these women were teenagers with 14% 16 years of age or less. Overall, 431 patients received Norplant implants insertions postpartum prior to discharge from the hospital. To date, 138 Norplant systems have been removed, with the proportion of contraceptive implant removals among teenagers being essentially the same as that in more mature women. Of the reasons given by women discontinuing the Norplant system, an unanticipated high incidence of pain in the arm containing the implants, hair loss, and mood changes were noted. We have found the Norplant system to be a highly effective and highly acceptable contraceptive method for a large number of indigent women.

BACKGROUND

Norplant is highly effective for long-term pregnancy prevention. Norplant users might not use condoms, and they may acquire human immunodeficiency virus (HIV) and other sexually transmitted diseases as a consequence.

OBJECTIVE

The goal of this study was to assess condom use among Norplant users at risk for sexually transmitted diseases.

METHODS

Telephone interviews were conducted with 177 sexually active Norplant users to measure risk for sexually transmitted disease and condom use.

RESULTS

According to the measures used in this study, 42% of the study subjects were at risk for sexually transmitted disease and 38% of those at highest risk did not use condoms.

CONCLUSIONS

Intervention to protect Norplant users from sexually transmitted disease is indicated.

Contraception remains an important part of national efforts to reduce adolescent pregnancy in the United States. A number of safe and effective contraceptive methods are available for our youth, including abstinence, barrier methods, oral contraceptives, Depo-Provera, and Norplant. Research over the past few decades has resulted in a variety of oral contraceptives with reduced amounts of hormones and reduced side-effects. A number of methods have received approval by the Food and Drug Administration since the last review in 1980, including emergency contraceptives, depomedroxyprogesterone acetate, and the cervical cap. The use of condoms and vaginal spermicides continues to be recommended for all sexually active adolescents to reduce (not eliminate) the risk for acquiring sexually transmitted diseases. A polyurethane condom is now available, in addition to the latex condom and other barrier contraceptives, including the following: diaphragm, cervical cap, vaginal sponge, female condom and vaginal spermicides. Because of continuing concerns about pelvic inflammatory disease related to intrauterine devices, currently available intrauterine devices are not recommended for most adolescents. Abortion is not considered as a contraceptive method.

As one element of Baltimore's effort to combat its high rate of teenage pregnancy, the Baltimore City Health Department added the implantable contraceptive Norplant to the array of services offered at one of its school-based health centers in early 1993. The initial findings with the adolescents who received this contraceptive at the school were favorable, particularly regarding condom use, parental involvement, and patient acceptance of the contraceptive. This new policy garnered a significant amount of attention, both nationally and locally. It attempts to address problems that have complicated etiologies as well as diverse clinical, social, and ethical ramifications, all complicated by political realities. The Norplant experience offers useful lessons regarding controversial health initiatives that address problems facing public health practitioners today.

The clinical research to date on the effects of 3 types of hormonal contraceptives, i.e. depot medroxyprogesterone acetate ('Depo-Provera'), levonorgestrel subdermal implants ('Norplant'), and oral contraceptives, on bone mineral density in premenopausal women is reviewed. The large variance in results across studies for each method is in part due to differences in research design, techniques for measuring bone mineral density, age of the study participants and type of oral contraceptive preparation. However, the balance of the evidence leans toward a positive effect of oral contraceptives on bone mineral density in women of all age. On the other hand, few observations have yet been published on the effects of the new progestin oral contraceptives on bone mineral density. The few extant data suggest a positive impact of levonorgestrel subdermal implants on bone mineral density in women of all ages. Although the findings are preliminary, it appears that depot medroxyprogesterone acetate may exert a negative effect on bone mineral density. More specifically, caution should be exercised in prescribing long term depot medroxyprogesterone acetate (e.g.>> 5 years) especially in young adolescents (e.g. < 16 years old) who may not have yet reached peak bone mass.

This cross-sectional study compares bone mineral density (BMD) in long-term Norplant implants and depot medroxyprogesterone acetate (DMPA) users. The objectives of this study were to evaluate and compare the bone mineral density between women using these contraceptives. Forty-one current users of Norplant implants and 50 DMPA users participated in the study. The BMD was measured by dual energy x-ray absorptiometry in the nondominant distal and ultradistal forearm. Serum estradiol was measured by microparticle enzyme immunoassay technique. The demographic characteristics were similar in both groups. The mean durations +/- SD of DMPA and Norplant implants were 59.14 +/- 30.73 and 31.1 +/- 11.2 months, respectively. The BMD of long-term Norplant implant and DMPA users was similar. The serum estradiol in the Norplant implant group was significantly higher than in DMPA users. However, the serum estradiol level in DMPA users ranged into normal for the follicular phase, which is higher than for postmenopausal women. This study suggests that two long-acting progestogen contraceptives do not differ with respect to their impact on BMD in long-term users.

OBJECTIVE

Levonorgestrel implants (Norplant) have recently been approved for use in the United States. Adolescents may be especially suited for this method of contraception because of its long duration of action and lack of dependence on patient compliance for efficacy. To date, however, its use in young patients has not been investigated. This study was undertaken to compare side effects and satisfaction with this new method during the first 6 months of use among adolescents and adults.

METHODS

Twenty-one adolescents 18 years of age or younger and 30 adults 19 years or older participated in this study. Information on side effects and satisfaction was obtained from clinic records and a structured interview conducted 6 months after insertion.

RESULTS

The most frequent reason adolescents gave for selecting Norplant was convenience. None of the adolescents were upset by the insertion process or by its appearance in the arm, although 10 (48%) reported that it was visible. The most frequent side effect reported by both adolescents (71%) and adults (53%) was abnormal menstrual bleeding. Weight gain was reported by 8 adolescents (38%), 3 of whom attributed it to an increase in their appetite. Other side effects commonly reported by adolescents included emotional disturbances (33%) and headaches (38%), whereas adults reported acne (27%) and mastalgia (37%). Only 1 adolescent (5%) and 1 adult (3%) reported experiencing no side effects. A similar percentage of adolescents (8%) compared with adults (6%) requested removal of the implant because of side effects during the 6-month period. Overall, satisfaction was expressed by 86% (18/21) of adolescents, all of whom stated that they preferred Norplant to their previous contraceptive method.

CONCLUSIONS

This investigation demonstrates that levonorgestrel implants are well tolerated by most young patients. Clinicians involved in the care of adolescents should consider Norplant as an appropriate option of birth control for this population.

OBJECTIVE

To compare attitudes and practices related to clinicians' use of depot medroxyprogesterone acetate [Depo-Provera (DMPA)] and levonorgestrel implants in adolescents in three northern European countries and the United States.

METHODS

Between the fall of 1993 and the winter of 1995, surveys eliciting clinician attitudes and practices with the two contraceptive methods were collected from practitioners who provide contraceptive care to teens in Sweden (n = 282), The Netherlands (n = 197), Great Britain (n = 108), and the United States (n = 548).

RESULTS

Clinicians in Great Britain and the United States reported prescribing of DMPA, selected DMPA in their top three choices for contraception in teens, and had patients ask about DMPA more frequently than clinicians in Sweden or The Netherlands (p < 0.0001). U.S. clinicians were more likely to report prescribing of the implants, list them as a top choice, and have patients ask for it more frequently than were providers in the other three countries (p < 0.0001). Noncompliance with previous contraceptives was the most common indication for use of either method in this age group. "Worst fears" with DMPA use included infertility, particularly among Swedish clinicians (p < 0.0001), as was pregnancy and loss to follow-up, particularly among British clinicians (p < 0.0001). Condom nonuse was a concern associated with both methods. Breakthrough uterine bleeding was a concern related to implant use, particularly among Swedish practitioners (p < 0.0001).

CONCLUSIONS

Clinicians in the United States and Great Britain display more enthusiasm toward the use of the long-term progestins in adolescents than do clinicians in Sweden or The Netherlands. Continuing education programs could be designed to educate clinicians to allay their concerns about these contraceptives in countries where teen pregnancy is considered a problem.

The purpose of this study was to examine the bleeding patterns of 234 Norplant users during 5 years of use and to identify the bleeding patterns of users who conceived. During the first year of use, 26.6% of users had regular bleeding cycles, 66.3% had irregular cycles, and 7.1% were amenorrheic. By the fifth year of use, 62.5% of users had regular cycles, 37.5% had irregular cycles, and none had amenorrhea. Of the ten users who became pregnant, eight had regular menstrual cycles in the 6 months before the diagnosis of pregnancy, one had an irregular pattern, and one did not keep a bleeding record. None had amenorrhea. The 5-years cumulative pregnancy rate for patients with regular cycles was 17.4%; this was significantly higher (P less than .05) than the 5-year cumulative rates of 4.4% in users with irregular cycles and 0% in users with amenorrhea. This study indicates that during the first year of Norplant use, only 26.6% of users have regular cycles, but after the first year, 50-60% of users develop regular cycles. The bleeding patterns of women using Norplant improve after the first year of use, and those with regular cycles are at greatest risk for method failure.

OBJECTIVE

To describe the complications reported at the removal of Norplant implants, and to suggest potential risk factors for these complications.

METHODS

Complications at the removal of Norplant implants from 3416 users from 11 countries who participated in preintroductory clinical trials of the method were tabulated. A logistic regression model was used to identify the significant risk factors associated with removal complications.

RESULTS

Complications were reported in 4.5% of removals; most often, they were related to broken or deeply placed implants. The most important risk factors were complications at insertion and having an infection at the implant site (at or before removal).

CONCLUSIONS

Proper insertion technique under aseptic conditions is very important in predicting whether Norplant implant removal will be difficult. Although relatively infrequent even now, more vigilant training and the evaluation of some of the newer removal techniques could further reduce the incidence of difficult removals.

The levonorgestrel-releasing IUD (LNG-IUD, 20 micrograms/d) and the Norplant-2 implants were studied in a randomized comparative clinical trial with 200 women for one year. No pregnancy or expulsion occurred with the Norplant-2. In the LNG-IUD group, there was one pregnancy at the 12th month of use after an unnoticed expulsion. The net cumulative pregnancy and expulsion rates of LNG-IUD were 1.0 and 3.0. The removal rate due to menstrual disturbances in both LNG-IUD and Norplant-2 groups was 3.0. The use-related discontinuation rates were 9.0 and 3.0, and the continuation rates were 90.0 and 96.0, respectively. The differences were not statistically significant. Menstrual disturbance was the main side effect. It was improved after long time use, especially in the LNG-IUD group. After one year, the percentages of women with amenorrhea were 18.9 for the LNG-IUD and 8.3 for the Norplant-2. The menstrual blood loss was statistically significantly reduced in the LNG-IUD group, and blood haemoglobin concentration increased in both groups. The LNG-IUD and Norplant-2 are highly effective, safe, long-acting, and well accepted by the Chinese women.

Medical and counseling staff at 13 family planning clinics in Texas, U.S.A., were surveyed regarding their opinions and level of information about the contraceptive Norplant. These responses were used to assess the relationships between clinicians' information and attitudes about the contraceptive and the use of that method by their patients. No differences were associated with respondents' clinical responsibilities or with their type of professional training. However, significant variations in the numbers of patients receiving Norplant from individual providers, and in the proportion receiving the method from certain clinics, were associated with responses to some attitudinal questions. These findings suggest that the opinions about Norplant held by personnel staffing family planning clinics influence the method selection of their patients.

OBJECTIVE

To provide scientific data regarding the changes in cervical mucus within the first hours to days after Norplant implant insertion and to estimate when the cervical mucus is hostile enough to suggest a contraceptive effect.

METHODS

Multicenter, clinical descriptive study.

METHODS

Family planning clinics.

METHODS

Forty-two women who were between days 8 and 13 of their menstrual cycle and who had requested Norplant implants were admitted to the study.

METHODS

Cervical mucus and blood samples were obtained.

METHODS

Cervical mucus scores, sperm penetration distances, and serum levels of progesterone, estradiol, and levonorgestrel.

RESULTS

The median cervical mucus score observed at baseline was 6 ("fair"), indicating that the mucus was already somewhat hostile before insertion of the Norplant implants. The median scores declined to 5 at 12 and 24 hours and continued to decrease through day 7 to 2 ("poor"), a score that is judged as hostile to sperm penetration. Overall, 73% of all subjects had a poor cervical mucus score by 3 days after insertion; at 7 days after insertion, 90% exhibited poor mucus and none had a good score. There was a substantial drop in the overall median distance traveled by the vanguard sperm after 12 hours for each cervical mucus score grouping. The distance traveled decreased rapidly between 12 and 24 hours to < 0.5 cm in subjects with fair and poor mucus, and by day 3, 91% of the subjects exhibited poor sperm penetration.

CONCLUSIONS

On the basis of our findings, deterioration of the quality of the cervical mucus and sperm penetration is evident by 24 hours after insertion, although not to a level that would suggest adequate protection until 72 hours after insertion. Therefore, we are confident in recommending that backup methods of contraception (e.g, condoms) need not be used for more than 3 days after insertion, even when the implants are inserted close to ovulation. These findings provide policy makers, clinic managers, and clinicians with important information about how they can improve client access to Norplant implants.

Two hundred and five women participating in a five-year clinical trial of NORPLANT and NORPLANT-2 were interviewed about their contraceptive and reproductive history, sources of information and knowledge of NORPLANT, experiences using the method, and the impressions of friends and family about the method. The most common reasons for trying the implants were dissatisfaction with other methods and perceptions about NORPLANT's ease of use. Forty-one percent of acceptors had anxiety prior to insertion; 49 percent of these feared pain, but only 5 percent said that they actually experienced significant pain. Women also feared implant removal, but their fear did not influence their decision to continue or discontinue use, and 74 percent reported little or no pain at removal. Most of the women were pleased with NORPLANT, although 95 percent reported side effects, with 82 percent reporting changes in menstruation. More than one-half of those women who discontinued reported that they would use the implants again. Seventy-four percent of the current users interviewed said they would like to use the implants in the future. For the women enrolled in the clinical trial, NORPLANT appeared to be a highly acceptable method of contraception, despite the frequent occurrence of bothersome side effects.

Two groups of implant users and two groups of IUD users participated in the study at different times. In the first groups, fractionation of lipoproteins was performed on serum samples from 28 subjects who had used the implants for 37 months and from 26 subjects who had used the Copper TCu 200 for 30 months. Users of the implants had significantly lower levels of total cholesterol, triglycerides and LDL-cholesterol than users of the IUDs. HDL-cholesterol levels were not different between the groups. In the other groups of women, general chemistries and selected hormone assays were carried out on samples from 30 subjects who had used implants for 51 months and from 24 subjects who had used the TCu 200 IUDs for 43 months. The parameters studied were the SM-12 chemistry group profile, estradiol, cortisol, testosterone, triiodothyronine, thyroxine and thyroid stimulating hormone. In the implant group, mean serum glucose levels were statistically significantly elevated and inorganic phosphorus levels were significantly reduced as compared to the IUD group. In both cases all individual measurements were within the normal range for the population. Testosterone and triiodothyronine levels in the implant group were significantly lower than in the IUD group, but no individual values were outside the normal range for the population. Mean values for all other parameters were not significantly different between the groups.

BACKGROUND

Endometrial breakthrough bleeding is characterized by an inflammatory reaction and increased production of proinflammatory mediators, one of which may be epithelial neutrophil-activating peptide-78 (ENA-78), a chemokine with neutrophil-activating properties.

RESULTS

We therefore investigated the endometrial expression of ENA-78 in Norplant users as progestin-only contraceptive with various bleeding patterns (n=35) as compared with non-users with a normal menstrual cycle (n=55). The endometrial stromal cells (ESCs) were the major site of ENA-78 expression with the highest levels found during the secretory phase. The expression of ENA-78 was increased in Norplant users with irregular bleeding as compared with those with regular cycles and amenorrhoea. The levels of ENA-78 detected in uterine washes and sera after the use of Norplant for 3-6 months (n=25) increased compared with baseline (P < 0.05). These levels did not significantly change in Norplant users who received doxycycline (Dox) therapy (25 mg/twice daily for 6 months) when measured midway through or at the conclusion of study when compared with the baseline (n=25). Treatments with medroxyprogesterone acetate (MPA) and tumour necrosis factor-alpha (TNF-alpha) (25 ng/ml), but not 17beta-estradiol (E2) or E2 + MPA (10(-8) M), representing endometrium exposed to contraceptive and inflammatory conditions, respectively, increased the levels of ENA-78 production by ESCs, and this was reduced by co-treatments with Dox (25 microg/ml) (P < 0.05).

CONCLUSIONS

The endometrial production of ENA-78 is altered in progestin-only contraceptive users experiencing breakthrough bleeding and is regulated by MPA and TNF-alpha in ESCs. Although Dox therapy did not alter uterine ENA-78 secretion, its suppression in ESCs suggests that Dox, acting site-specifically and through an anti-inflammatory mechanism, may influence the outcome of breakthrough bleeding in contraceptive users.

Blood glucose and plasma insulin levels during an oral glucose tolerance test were measured in 20 women using continuous subdermal levonorgestrel (Norplant) for contraception over a 12-month period. Changes in carbohydrate metabolism occurred as early as 1 month but were most marked after 6 months. After 1 month the area under the glucose and insulin curves increased by 12.3% and 37.7%, respectively. This increase was more marked by 6 months, but by 12 months it was significantly less marked. Although changes in the blood glucose and plasma insulin levels at different times during the oral glucose tolerance test occurred, they were all within normal limits for normal women. The peak blood glucose and insulin levels after insertion of the implant occurred 60 minutes after the glucose load, as opposed to 30 minutes before insertion. Apart from this, there was a significant delay in the return of these levels to fasting values. We conclude that this product, like any other progesterone-containing contraceptive, alters carbohydrate metabolism, but these alterations are not clinically significant in normal women. It is, however, possible that in potential cases of diabetes it may predispose to frank diabetes.

1. Endothelin (ET) and its mRNA are present in endometrium. Expression of ET varies across the menstrual cycle, reaching maximal levels in the premenstrual phase, suggesting a paracrine role in endometrial bleeding and/or repair. 2. The major cellular source of ET is the epithelium, although endothelium and decidualized stroma are additional sites of production. Epithelial ET is the ET-1 isoform and this is able to contract rat thoracic aortic rings ex vivo. 3. Endothelin-1 production by cultured endometrial epithelial cells is markedly increased by serum and, to a lesser extent, by transforming growth factor-beta and interleukin-1 alpha, but not by epidermal growth factor, oxytocin, arginine vasopressin, thrombin or angiotensin II, which stimulate ET production in other tissues. 4. Endothelin-1 has mitogenic actions on endometrial stromal cells; it stimulates the uptake of [3H]-thymidine, acting via the AP-1 cis element c-jun. 5. Neutral endopeptidase (NEP), a membrane-bound ectoenzyme that is capable of degrading ET, is localized principally in endometrial stroma and immunoreactivity is maximal in the secretory phase of the cycle. 6. A potential role for ET in regulating endometrial bleeding is suggested by studies on endometrium from two groups of women who were experiencing abnormal uterine bleeding: users of the contraceptive Norplant (Leiras Co., Turku, Finland) and subjects with documented menorrhagia. In both groups, ET-1 immunoreactivity in endometrial epithelium was markedly reduced compared with the normal menstrual cycle and did not vary cyclically, while NEP immunoreactivity, particularly in the epithelium, was increased. Thus, ET may be involved in endometrial bleeding, as a vasoconstrictor before the onset of menstruation when vasoconstriction is intense and, subsequently, when it may be required in the cessation of menstrual bleeding. Furthermore, the mitogenic actions of ET may play a role in endometrial regeneration and remodelling during the menstrual cycle, particularly following menstruation.

The first controlled-release methodology was developed in 1962 and was based upon diffusion of small molecules (molecular weight less than 500) through the wall of silicone rubber tubing. The problem of controlled-release of large molecules such as proteins was not solved until more than a decade later, when it was discovered that microchannels formed around lyophilized proteins embedded in polymers such as ethylene vinyl acetate copolymer (EVA) and poly(hydroxyethylmethacrylate) (pHEMA), as water permeated through the polymer. These studies led to the development of a 5-year contraceptive implant, e.g., Norplant; rapid progress in the field of angiogenesis research; and a method for regulating cell shape and growth control in vitro.