Plasma levels of cortisol and corticosteroid binding globulin (CBG) were studied during one year in eleven healthy women using NORPLANT-2 implants. NORPLANT-2 implants release approximately 50 ug of levonorgestrel/day. A significant diurnal variation of cortisol levels was found during the study. No significant change in cortisol levels compared to pretreatment levels was found. Levels of CBG showed no diurnal variation, but decreased significantly during use of the implants. This was most probably due to a direct effect of the levonorgestrel, as the levels of estradiol did not change compared to pretreatment levels, except for the values after 6 months that were significantly lower than pretreatment levels. A "free cortisol index" calculated as: level of cortisol/level of CBG, was unchanged during treatment compared to pretreatment levels. It is concluded that although CBG levels were reduced, no significant change in cortisol patterns was seen during use of the implants.

The NORPLANT system is one of the most modern long acting steroidal fertility regulatory delivery systems to be introduced. It consists of six silicone capsules. The NORPLANT-2 rod system on the other hand consists of only 2 rods. The comparative study undertaken suggests that the NORPLANT-2 rod system is highly effective, safe and acceptable as the NORPLANT six capsule system in Singapore. It would thus appear that the NORPLANT-2 rod system as compared to the NORPLANT six capsule system has a great potential for acceptability in terms of ease of insertion and removal.

Six Silastic levonorgestrel-releasing capsules, Norplant, were introduced subcutaneously into the ventral aspect of the left forearm or upper arm of thirteen patients immediately after first trimester pregnancy termination. Blood samples were taken twice a week over two months after abortion and from one subject over one month after removal of Norplant capsules. Plasma concentrations of levonorgestrel were measured by radioimmunoassay and the effects of treatment on pituitary and ovarian function were determined by assaying plasma concentrations of LH, FSH, estradiol and progesterone. If removal of Norplant capsules took place because of planning pregnancy, the subjects were asked to inform us if they had become pregnant. During the first month after abortion the mean levonorgestrel concentration (489 pg/ml) was statistically significantly higher than during the second month (237 pg/ml). The mean estradiol values fell to prefollicular levels within four days, remaining a little suppressed. The mean progesterone concentrations were below 2 ng/ml three days after abortion. Three subjects had a transient increase in plasma progesterone concentrations nine days after abortion. Thereafter no ovulatory progesterone concentrations were seen. The LH concentrations ranged within normal values of the follicular phase and FSH values were just beneath the lower limit of follicular phase FSH values, apart from a few peaks, indicating mild suppression. After removal of Norplant capsules, progesterone concentrations increased to ovulatory levels fifteen days after removal. The Norplant capsules were removed from two subjects because of planning pregnancy and they delivered healthy babies 9.5 and 12.5 months after removal.

The subcutaneous implants from the levonorgestrel (Norplant) has been introduced in Burkina Faso in September 1992 within the context of a project assisted by a non-governmental organization (the Population Council). The aim was to reinforce the family planning programme in Burkina Faso by increasing the number of family planning methods available for the clients. 4 years after its introduction, we propose to make a report of our experience in terms of the contraception through subcutaneous implants in order to better set up an IEC campaign on this method. Within 4 years, 1,660 users benefitted from that contraceptive method. They were housewives in 65% of the cases. The age-group of 30-34 years old most used this method with 28.6%. Multipares most benefitted from this method with 64.3%. In 72% of the cases, the insertion was made during the premenstrual period. On the whole, 247 withdrawals have been made before the fourth years for various reasons. Among those reasons are cycle disorders (60 withdrawals), medical reasons (53 withdrawals), personal conveniences (47 withdrawals), weight gaining (14 withdrawals), failures (2 withdrawals). Regarding the side effects, they were mainly represented by the menstrual cycle disorders such as amenorrhoea, spotting, hypermenorrhoea in 51% of the cases. A good information and sensitization campaign should reduce the number of implants withdrawals before the fourth year of use. Moreover, a perfect knowledge of contraindications is indispensable before any prescription.

Family planning groups and a lawmaker accused a US drug company yesterday of profiteering on Norplant, the implantable, 5-year contraceptive. The company said its $365 product is cheaper than birth-control pills. But Rep. Ron Wyden said Norplant was developed with extensive government support and sells for $23 in some Third World countries. He said its cost to Wyeth-Ayerst laboratories may be as little as $16. About 875,000 US women have had 6 match-sized hormone-dispensing rubber capsules implanted in their upper arms since 1990. Dr. Amy Pollack of the Association of Reproductive Health Professionals said 56% of the 6 million pregnancies in the US each year are unwanted. She said 1.7 million pregnancies occur among women using contraceptives. The failure rate is less than 4 per 10,000 with Norplant compared with 3 per 100 women on the pill, she said. Dr. Marc W. Deitch, Wyeth's medical director, said the company made a risky decision to bring Norplant to market in collaboration with the nonprofit Population Council. The implant costs women 20 cents a day over its 5-year life, said Dr. Deitch. The $365 cost is significantly less than the $1481 they would pay over 5 years for birth-control pills, $762 for a diaphragm and $590 for shots of Depo Provera, he said. Male condoms cost $312 and an IUD $176. Family planning advocates challenged Dr. Deitch's math. Judith DeSarno, president of the National Family Planning and Reproductive Health Association, said federally funded clinics pay only $60 for a 5-year supply of oral contraceptives. Women also must pay doctor fees--usually from $150 to $200--for inserting Norplant and eventually removing it from their upper arms.

In this longitudinal study involving 100 Singaporean acceptors, the effects of NORPLANT on their metabolic function was evaluated. With respect to liver function, the results indicate possible hepatocellular dysfunction; there was a significant rise in mean serum bilirubin from 0.55 mg/dl to 0.87 mg/dl after 12 months of use (p less than 0.001). This rise could not be attributed to a skewed distribution of mean value as the difference achieved statistical significance using the paired 't' test as well as the Wilcoxon signed rank test using the median distribution. In terms of the effects of NORPLANT on lipid metabolism, we have demonstrated a significant rise in HDL-cholesterol (1.08 mmol/l +/- 0.34 to 1.13 mmol/l +/- 0.24; p less than 0.05) with significant decreases in mean serum triglycerides (1.21 mmol/l +/- 0.74 to 0.89 mmol/l +/- 0.45; p less than 0.002) and total cholesterol (5.05 mmol/l +/- 1.02 to 4.64 mmol/l +/- 0.81; p less than 0.001) after one year of use. There was also a significant rise in the HDL-cholesterol/total cholesterol ratio after 1 year (0.225 +/- 0.086 cf 0.250 +/- 0.059; p less than 0.001). As we have not incorporated a simultaneous non-pill treated control group, the observed changes in lipoprotein lipids could be attributed to extraneous factors such as diet, exercise or other environmental changes. Nevertheless, the findings though speculative indicate NORPLANT use to be non-contributory to cardiovascular risk and indeed it may be protective factor against such risks in this population. The use of NORPLANT was not associated with any significant effect on glucose tolerance after 12 months of use.

In this longitudinal study involving 100 Singaporean acceptors, the effects of Norplant-2 rods on metabolic function was evaluated. With respect to liver function, the results indicate possible hepatocellular dysfunction. There was a significant rise in mean serum bilirubin from 0.54 mg/dl to 0.85 mg/dl after 12 months of use (p less than 0.001). Furthermore, there was also a significant fall in total proteins from 7.37 gm/dl to 7.12 gm/dl (p less than 0.001) and serum globulin from 3.18 gm/dl to 2.84 gm/dl (p less than 0.001). As regards lipid metabolism, we have demonstrated significant decreases in mean serum triglycerides (1.04 mmol/l to 0.83 mmol/l), p less than 0.001; total cholesterol (5.04 mmol/l to 4.64 mmol/l), p less than 0.001; and LDL-cholesterol (3.36 mmol/l to 3.10 mmol/l), p less than 0.001 after one year of use. There was a small fall in the HDL-cholesterol (1.21 mmol/l to 1.16 mmol/l) after 12 months of use; this fall was not significant. Despite this, there was a rise in the HDL-cholesterol/Total cholesterol - HDL-cholesterol ratio (0.258 cf 0.244; p less than 0.05) after 1 year of use. As we have not incorporated a simultaneous non-pill treated control group, the observed changes in lipoprotein lipids could be attributed to extraneous factors such as diet, exercise or other environmental changes. Nevertheless, the findings, though speculative, indicate Norplant-2 use to be non-contributory to cardiovascular risk and indeed it may be a protective factor against such risks in this population. The use of Norplant-2 rods was not associated with any significant effect on glucose tolerance after 12 months of use.

In this longitudinal study involving 100 Singaporean acceptors, the effects of Norplant on metabolic function was evaluated. With respect to liver function, the results at the end of two years still indicate the presence of possible hepatocellular dysfunction. Despite a 4.5% decrease in serum bilirubin during the second year, the mean serum bilirubin still remained significantly raised (p less than 0.001). Furthermore there was a significant fall in total proteins and globulin during the period under review (p less than 0.001). However mean levels of all three parameters remained within the normal clinical range. As regards lipid metabolism, the total triglycerides and total cholesterol still remained significantly decreased at the end of two years (p less than 0.001). The LDL-cholesterol, which was significantly decreased at the end of one year, increased by 2.2% during the second year. However, this rise in LDL-cholesterol was not significant and was still below the preinsertion level. The HDL-cholesterol levels returned to their preinsertion levels after a significant increase in the first year. The HDL-cholesterol/Total cholesterol - HDL-cholesterol ratio returned to its preinsertion value at the end of two years while the LDL-cholesterol/HDL-cholesterol ratio was still significantly lower than the preinsertion ratio (p less than 0.05). As we have not incorporated a simultaneous non-steroid treated control group, the observed changes in lipoprotein lipids could be attributed to extraneous factors such as diet, exercise or other environmental changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Levonorgestrel is a commonly used progestin-only contraceptive that is available as subdermal (Norplant) and intrauterine implants. Other progestin-only contraceptives such as injectable medroxyprogeterone acetate have been shown to decrease bone mineral density in long-term users. We used calcaneal ultrasound to compare the bone quality of Nigerian women between 25 and 50 years of age who had Norplant implants for 1-4 years to that of women who were not using any form of hormonal contraceptive. The mean stiffness index of women who had Norplant implants for as long as 4 years was not significantly different from that of controls. However, serum markers of bone turnover were significantly decreased in women with Norplant implants compared to age-matched controls. Serum bone-specific alkaline phosphatase was significantly decreased in subjects with Norplant implants for 1 year (13.7+/-6.0 vs. 23.0 U/L for controls, p = .001) and serum NTx was significantly decreased in subjects with implants for 3 years (10.6+/-4.9 vs. 17.6+/-7.7 bone collagen equivalents per liter for controls, p < .001). We conclude that although levonorgestrel contraceptive decreased overall bone turnover, it had no deleterious effect on the bone quality of women using Norplant implants for up to 4 years.

In a longitudinal study involving 100 Singaporean women, the effect of NorplantR on metabolic function was evaluated. With respect to liver function, the results indicate possible hepatocellular dysfunction as evidenced by a significant rise in serum bilirubin and a significant fall in total proteins and globulin during the period under review. As regards lipid metabolism, total triglycerides and total cholesterol still remained significantly decreased at the end of the three years. The LDL, which was significantly decreased in the first year, increased during the subsequent two years to its preinsertion value at the end of three years. The HDL-cholesterol levels continued to decrease in the second and third year after a significant increase in the first year. Despite this, the HDL cholesterol/total cholesterol-HDL cholesterol remained above 0.200. As we have not incorporated a simultaneous non-pill treated control group, the observed changes in lipoprotein lipids could be attributed to extraneous factors such as diet, exercise, or other environmental changes. Nevertheless, the findings at the end of three years, though speculative, still appear to indicate Norplant use to be not directly contributory to cardiovascular risk. The use of Norplant was not associated with any significant effects on carbohydrate metabolism after three years of use.

Subdermal Norplant-2 implantation, developed for contraception based on sustained release of levonorgestrel, has already been conducted in many countries around the world. From October 1986 to November 1988, a total of 267 female volunteers were enrolled in Norplant studies at the National Taiwan University Hospital. After a follow-up of 36 months, only one of the 231 evaluable cases (0.4%) became pregnant. The continuation rate was 84.5%, 61.3%, and 52.0% at the end of 12, 24 and 36 months after insertion, respectively. Menstrual problems were the most common adverse effects and were also the main reason for discontinuation. In the 23 patients who wished to become pregnant, fertility occurred soon after removal of the Norplant implant. After insertion, serum total cholesterol and triglyceride levels significantly decreased and the hemoglobin concentrations were increased. No liver or renal toxicities were detected. The data suggest that Norplant-2 is a highly effective, safe and long-acting method of reversible contraception. It would be worthwhile to introduce this contraceptive system into Taiwan's family planning program.

OBJECTIVE

Norplant has been widely used in Indonesia, though a previous study conducted in Jakarta indicates that there is a significantly high cholesterol level in acceptors. Other international studies indicate different results. Accordingly, a study on the fraction of blood lipids of Norplant acceptors was considered necessary. MATERIAL AND PROCEDURES: A prospective cohort comparative study was conducted in the Dr Kariadi General Hospital and Primary Health Center at Gunungpati. Clinical and laboratory observations were done by means of pre-post test design. Norplant acceptors were treated as the case group while IUD acceptors were the control group. Cholesterol level, triglyceride, HDL, LDL, and ratio of cholesterol:HDL, side-effects and continuation of use were evaluated.

RESULTS

The subjects were 91 Norplant and 89 IUD acceptors. Norplant acceptors showed the following study results: Total cholesterol showed a slight decrease (165.06-132.80 mg/dl), triglycerides were slightly increased (76.23-81.87), HDL showed a decrease (45.55-38.85), and so did LDL (105.75-78.55); the ratio of cholesterol:HDL remained constant (3.75-3.78) and all fraction levels of blood lipids were within the limit of tolerance and did not exceed the critical value. Normal menstrual blood flow remained constant, but heavy menstrual blood flow decreased. The cycle of normal menstruation was reduced and the inter-menstrual bleeding and the 2-3 month menstrual cycle were increased. Complaints of dizziness/headache, leucorrhea, and pain at insertion were all relatively few. There was no change of body weight and blood pressure. Continuation of use was 100%.

CONCLUSIONS

The fraction of blood lipids found indicates varied results though blood lipids are still below critical values; it can be concluded that there is no risk of coronary heart disease. The continuation rate of Norplant use was high, due probably to side-effects counseling, and the social and cultural circumstances of acceptors.

In this longitudinal study involving 100 Singaporean women, the effects of Norplant-2 rods on metabolic function were evaluated. With respect to liver function, the results indicate possible hepatocellular dysfunction as evidenced by a significant rise in serum bilirubin and a significant fall in total proteins and globulin during the three years of use. As regards lipid metabolism total triglycerides, cholesterol and LDL cholesterol were significantly decreased as compared to their preinsertion values at the end of three years. The HDL-cholesterol was also significantly decreased during the second and third year of use. Despite this, the HDL-cholesterol/total-cholesterol-HDL-cholesterol remained above 0.200. Thus, though speculative, it still appears to indicate that use of Norplant-2 rods is not directly contributory to cardiovascular risk. The use of Norplant-2 was not associated with any significant effect on carbohydrate metabolism after three years of use.

OBJECTIVE

This study was undertaken to assess the efficacy, acceptability and side-effects of the Norplant (Leiras) contraceptive system during adolescence.

METHODS

A total of 13 adolescents were implanted with Norplant immediately after menstruation. Adolescents were advised to present for follow-up visits at 3 days after implantation, at 3, 6 and 12 months and every 1 year thereafter. Blood pressure, menstrual disorders, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, glucose and side-effects were recorded at every visit.

RESULTS

The follow-up period was 24 months with a continuation rate of 100% (13/13) for the first 6 months, 92.5% (12/13) for 12 months and 53.8% (7/13) for the whole period. No pregnancies were observed. No infections at the implant site or expulsions were observed. Menorrhagia was observed in 4/13 (30.76%) adolescents in the third month. Thereafter all adolescents were treated with tenoxicam (prostaglandin synthetase inhibitor), so that by the end of the sixth month of treatment menorrhagia was not present in any of the 13 adolescents. No increase of blood pressure was observed. A statistically significant increase (p < 0.01) of triglycerides at 6 months after implantation was found; however, no difference was observed in the values of serum glucose, total cholesterol, HDL and LDL.

CONCLUSIONS

This preliminary study has shown that Norplant is acceptable as a contraceptive method among adolescents in Greece and can be prescribed safely.

The effect of Norplant-2 rods on liver function and lipid metabolism was evaluated in 100 Singaporean women. As with the Norplant six-capsule, the only change noted in liver function was that of a significantly elevated bilirubin, which was within the normal clinical range for the local population. As regards lipid metabolism, the mean values for total triglycerides, cholesterol, LDL-cholesterol and HDL-cholesterol seen at the end of five years of Norplant-2 rod use and six months postremoval were similar to the preinsertion mean. As a result, the HDL-cholesterol/total-cholesterol-HDL-cholesterol and LDL-cholesterol/HDL-cholesterol ratio remained fairly constant. This indicates that the use of Norplant-2 rods does not directly contribute to cardiovascular risk.

OBJECTIVE

This study reports the results of the lipid profile and oral glucose tolerance test (OGTT) in 46 normal patients tested before and after 5 years of Norplant use.

RESULTS

After 5 years, there was a substantial decrease of 28.9% in high-density lipoprotein cholesterol levels and a similar but less pronounced fall of 7.1% in the total cholesterol levels. The Castelli 1 index did not vary, and the triglycerides and low-density lipoprotein cholesterol levels remained normal and unchanged throughout the study period. All the mean values of OGTT were significantly lower after 5 years, except for the 90-min glycemia.

CONCLUSIONS

These findings indicate that long-term Norplant use does not increase cardiovascular risks.

Cholesterol content of major lipoprotein fractions along with total cholesterol (Tc) and triglyceride (Tg) were measured in 65 samples from 35 women using levonorgestrel contraceptive implant, Norplant-2 from the third month of implantation until the end of second year along with twenty-five healthy controls. There were significant decreases in all the fractional lipid values, Tc and Tg, up to the sixth month followed by a gradual rise of all lipid parameters except HDLc which remained much below the control level. Interestingly, VLDLc exhibited a significant rise at the end of the second year.

Twenty-five women using the levonorgestrel-containing contraceptive implant, Norplant-2, were studied longitudinally, to see the effects on lipid profile, glucose tolerance and hepatic transaminases with short-term (12 weeks) and long-term (18 to 24 months) use of Norplant-2 [corrected]. Total lipids, cholesterol, phospholipids, triglycerides and their subfractions were evaluated. There was a significant increase in LDL-cholesterol after 12 weeks of use (p less than 0.05), which did not persist at 18-24 months follow-up. The HDL-cholesterol, HDL/LDL-cholesterol ratio, phospholipids, other lipid fractions, hepatic transaminases and glucose tolerance did not alter significantly following short-term or long-term use of Norplant-2.

OBJECTIVE

To determine the effect of Norplant on plasma immunoglobulins, albumin and total proteins.

METHODS

A longitudinal prospective study of Norplant (six capsules) subdermal contraceptive implant acceptors.

METHODS

Family Planning Clinic, University College Hospital, Ibadan, Nigeria.

METHODS

36 women volunteers aged 18-40 years on Norplant.

METHODS

Serum immunoglobulins, albumin and total protein before, one, three and 12 months after Norplant insertion.

RESULTS

No statistically significant changes were observed in plasma levels of IgA, IgM and total proteins but plasma levels of IgG showed statistically significant increases after one, three and 12 months on Norplant.

CONCLUSIONS

Norplant does not seem to alter IgM, IgA, albumin and total protein levels over a period of 12 months. It, however, induces significant changes in IgG levels at one, three and 12 months after insertion. These changes are less marked by the end of 12 months.

OBJECTIVE

To assess the safety of Norplant contraceptive implant use by women with mild-moderate homozygous sickle cell disease (HbSS).

METHODS

Prospective observation of women pre- and post-insertion of Norplant, with each woman serving as her own control.

METHODS

25 women 18-40 years of age who attended a hospital sickle cell clinic; post-insertion data were available for 23 women.

METHODS

Changes in hematologic parameters including PCV, MCV, reticulocytes, ISCs, HbF and bilirubin; changes in biochemical parameters including HDL cholesterol, aspartate transaminase, alkaline phosphate, serum creatinine and serum albumin.

RESULTS

With a mean follow-up of 12.4 months (range 1-29 months), there were no clinically or statistically significant group or individual changes in the hematologic or biochemical parameters after Norplant insertion.

CONCLUSIONS

Norplant appears to be a safe and appropriate contraceptive for women with mild-moderate HbSS disease.

A previous report has shown that progesterone up-regulates cathepsin D expression in human endometrial cell culture. In women using the levonorgestrel-releasing Implant Norplant, the plasma levonorgestrel and immunoreactive endometrial progesterone receptor concentrations are elevated. However, the functional status of these receptors is not known. This study used endometrial cathepsin D expression both as an indirect marker for the functional status of endometrial progesterone receptors, and to identify the cell types that express cathepsin D. The results show that cathepsin D is primarily found in glandular epithelia and luminal epithelia in control and Norplant endometria. There is no significant difference in cathepsin D expression between the control and Norplant endometria, between the various stages of the menstrual cycle, or between Norplant users with varying degrees of breakthrough bleeding. Cathepsin D is also detected in cells scattered in the stroma in both control and Norplant endometria. The majority of these cells are macrophages. These data indicate that there is no evidence for progesterone regulation of cathepsin D in the human endometrium. Cathepsin D thus cannot be used as a marker for the functional status of progesterone receptors found in the Norplant-exposed endometrium.

The objective of this study was to measure oestradiol, progesterone and endometrial development among Norplant implant users with bleeding complaints. Seventy-six volunteers complaining of prolonged/frequent bleeding were enrolled. Oestradiol, progesterone and endometrial thickness (assessed by vaginal ultrasound) were determined at that visit. Two thirds of the women had low oestradiol (< 50 pg/ml) and all except one had low progesterone concentrations (< 3 ng/ml). A total of 68% had a very thin endometrium (< 3 mm). A subgroup of 21 women were followed twice a week for 8 consecutive weeks. Oestradiol and progesterone concentrations remained low during the continuous bleeding episodes or short bleeding-free intervals (< or = 15 days), yet increased five- to sixfold (253.4 +/- 142.2 pg/ml) in long bleeding-free intervals. Endometrial thickness remained thin irrespective of the differences in bleeding patterns and oestradiol. We conclude that Norplant implant users with bleeding complaints are usually characterized by low oestradiol concentrations, absence of luteal activity and thin endometrium. A good correlation exists with increasing oestradiol concentrations and longer bleeding-free intervals, but this is not manifested by increased endometrial thickness. However, few subjects bleed with relatively high oestradiol concentrations, therefore a better understanding of the intimate disturbances related to endometrial bleeding in users of long-acting progestins is still pending.