Plasma levonorgestrel and progesterone levels in women treated with silastic covered rods containing levonorgestrel

Levonorgestrel and progesterone plasma levels were measured in women bearing levonorgestrel subdermal implants. Two groups using four or six levonorgestrel covered rods and one group of non-hormonal contraceptors were compared. Blood samples were drawn twice a week for six consecutive weeks at different intervals after treatment administration.

The mean levonorgestrel levels (X ± S.D.) observed in the four rods group was .49 ± .13 ng/ml in the first year and decreased to .34 ± .06 in the fifth year of treatment. The mean values observed in the six rods group were .70 ± .15 ng/ml in the second year and .43 ± .11 in the sixth year. The levonorgestrel plasma levels were slightly above those found with NORPLANT^R implants in the four rods group and well above it in the six rods group.

The highest plasma progesterone value found in each sampling period was above 9 nmol/l in 7 (14%) out of 50 subjects in the four rods group, in 2 (4.3%) out of 47 subjects in the six rods group and in all the 49 control women. In 4 out of the 7 subjects from the 4 rods group and in the two subjects from the 6 rods group, the highest progesterone value was preceded and followed by values lower than 6 nmol/l. It was concluded that the progesterone levels were seldom compatible with the occurrence of ovulation in women treated with four or six levonorgestrel covered rods which release an estimated daily dose of 70 and 105 ug, respectively.     

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.     

Cholesterol and HDL-cholesterol values in women during use of subdermal implants releasing levonorgestrel

Plasma concentrations of cholesterol, HDL-cholesterol, and levonorgestrel were determined in two groups of women using levonorgestrel-releasing subdermal implants. One group used six capsules (NORPLANT)*; the other six covered rods. Plasma concentrations of levonorgestrel among NORPLANT users averaged 700 pg/ml in the first two weeks of use, decreased to 300 pg/ml at 8 weeks, and to about 230 pg/ml by 50 weeks. Concentrations among covered rod users were 1.4 to 1.7 times higher at comparable time periods. Total serum cholesterol and HDL-cholesterol were decreased as compared with controls at all sampling intervals during the 114 weeks of the trial, although the differences did not meet tests of significance at all time periods. Decreases during the test period were of the order of 10 percent, except for total cholesterol among covered rod users where the decrease was less. Cholesterol to HDL-cholesterol ratios did not differ significantly from control values at any sampling period.     

Androgen levels in women using Norplant implants

Plasma concentrations of sex hormone binding globulin (SHBG), testosterone, free testosterone, androstenedione (A4) and levonorgestrel were studied in 17 women before and during use of two levonorgestrel covered rods resulting in identical plasma concentrations of levonorgestrel as Norplant implants. There was a highly significant decrease in SHBG during treatment. Total testosterone and A4 also decreased significantly. Free testosterone remained unchanged. Diurnal variations were found to occur for A4, total and free testosterone, but not for SHBG or levonorgestrel. Moreover, plasma concentrations of testosterone, free testosterone, levonorgestrel and SHBG were measured in a second group of 88 women participating in a clinical study on Norplant implants, who at the one year follow-up visit either denied or claimed to have developed increased facial acne during treatment. There was no difference regarding SHBG, total testosterone, free testosterone or levonorgestrel between the groups of women with and without facial acne. However, the women in the group noticing increased acne during treatment, reported significantly more often to have had acne before treatment compared to the women who did not notice increased acne during treatment. It is concluded that treatment with Norplant implants does not result in increasing plasma levels of androgens.     

Contraception with long-acting subdermal implants. A five-year clinical trial with Silastic covered rod implants containing levonorgestrel. The International Committee for Contraception Research (ICCR) of the Population Council

A total of 189 women volunteered to accept subdermal implants for contraception. The implants were "covered rods", consisting of a core rod containing equal parts by weight of levonorgestrel and polydimethylsiloxane and sealed inside a thin-walled tube of Silastic tubing with medical adhesive. In one study 78 women used 4 3cm rods (study 07) and in the other 111 women used 6 3cm rods. In 5 years of use there were no pregnancies in either group. Terminations because of menstrual problems were twice as frequent among the 4-rod users than among users of the 6 rods. Menstrual pattern analysis is presented for the two rod regimens and compared with the previously reported patterns for the 6-capsule regimen (NORPLANT). Long--term in vivo release rates are also presented.     

Immediate postabortal contraception with Norplant: levonorgestrel, gonadotropin, estradiol, and progesterone levels over two postabortal months and return of fertility after removal of Norplant capsules

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.     

Release rates of levonorgestrel from silasticR capsules,homogeneous rods and covered rods in humans

Three forms of subdermal implants containing levonorgestrel are described. These are: capsules, in which the powdered drug is sealed inside of lengths of Medical Grade Silastic tubing; homogeneous rods, in which the drug is uniformly dispersed in Silastic 382 Medical Grade Elastomer; and covered rods, in which a core rod of drug and filler-free polydimethyl-siloxane polymer (50:50, Wt:Wt) are sealed inside thin-walled Silastic tubing.Long-term $\text{in vivo}$ release rates from human subjects are presented; 6.5 years for capsules, 3.6 years for homogeneous rods and 4 years for covered rods. Sets of six capsules release a decreasing amount of drug through the first few hundred days $\text{in situ}$ and after 500 days a fairly constant rate of about 35 micrograms per day is released (2 μg/cm). Homogeneous rods deliver a continuously declining amount of drug during the entire time studied. In the first 100 days the release averages 136 micrograms per day from a set of three 3-cm rods (15 μg/cm), gradually declining to 30 micrograms per day (3.3 μg/cm) from day 800 to day 1300. The covered rods deliver at a constant rate of 17.5 micrograms per day for a 3-cm rod (5.83 μg/cm) through 4 years.     

Clinical and endocrinologic study of continuous levonorgestrel administration from subcutaneous solid polydimethylsiloxane rods

Three solid polydimethylsiloxane (Silastic) rods containing levonorgestrel were inserted into the subcutaneous tissue of the volar aspect of the forearm of 8 women. Serum samples were drawn three times a week for 2 months and weekly thereafter for 2 years in 3 of the subjects. The other subjects had serum drawn during the twelfth and last treatment months. Levonorgestrel, estradiol and progesterone were measured in all samples. The subject kept a bleeding record. In comparison to an earlier clinical trial in which 6 hollow capsules of Silastic filled with levonorgestrel were used, the 3 solid levonorgestrel-containing rods provided higher serum levels of levonorgestrel, fewer serum estradiol peaks, only a single episode of ovulation and better bleeding performance.     

Long-term follow-up of women treated with NORPLANT implants

This report describes the long-term follow-up of 376 women who received NORPLANT^R 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^R 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^R 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^R 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^R 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^R implants suggests that these changes are reversible.     

Levonorgestrel in milk and plasma of breast-feeding women with a levonorgestrel-releasing IUD

A levonorgestrel-releasing intrauterine contraceptive device was used by 10 breast-feeding women beginning 6 weeks after delivery. Two models of IUD were used. One released 10 microgram (5 patients), the other 30 microgram (5 patients) of levonorgestrel per day. Plasma and milk samples were collected 8 times over a 3-month period and the concentrations of levonorgestrel determined by radioimmunoassay. An improved and sensitive method for the determination of levonorgestrel in milk was developed. A column chromatographic purification of a milk extract before radioimmunoassay made possible the use of large milk samples in order to improve the sensitivity. The plasma concentrations during the follow-up period were 207 +/- 64 pg/ml (mean + SD) in the 10 microgram and 235 +/- 87 pg/ml in the 30 microgram/day releasing IUD groups. The milk levonorgestrel concentrations were 56 +/- 35 and 57 +/- 34 pg/ml, respectively. The plasma to milk ratio of levonorgestrel was initially 100:15 and at the end of the 3-month follow-up period 100:25. There were no significant differences in the milk and plasma concentrations between the study groups. The total amount of levonorgestrel excreted per day in 600 ml breast milk is approximately 0.1 per cent of a daily dose of 30 microgram.     

Anovulation, inadequate luteal phase and poor sperm penetration in cervical mucus during prolonged use of Norplant implants

Blood samples for progesterone assay were collected for a total of 49 cycles, from 27 volunteers using the NORPLANT system. Levonorgestrel determinations were carried out in the same samples. A group of 12 women with normal cycles were studied in the same manner to serve as controls. Of the 49 cycles studied, 20 (41%) were ovulatory. The mean levonorgestrel level in ovulatory patients was 0.34 +/- 0.11 ng/ml (S.D.) compared to 0.42 +/- 0.14 ng/ml (S.D.) in anovulatory cycles. Compared to the control group, progesterone levels were significantly lower for users of NORPLANT implants during days -12 to -10 (p less than 0.025), -9 to -7 (p less than 0.05), -6 to -4 (p less than 0.0005) and days -3 to -1 (p less than 0.01). Cervical mucus evaluations and post-coital tests were done around mid-cycle in 29 of the cycles studied. All samples of cervical mucus were of poor quality, viscous and scarce, with a mean SPK of 4.1 +/- 2.3 cm. Most had absent or atypical ferning. Twenty-one subjects (73%) had a post-coital score of 1, and 4 (14%) of zero. Thus, anovulation, inadequate luteal phase and the direct effect of the continuous administration of levonorgestrel over cervical function, all seem to contribute to the effectiveness of NORPLANT implants.     

The effect of levonorgestrel and estrone rods on male reproductive function

The effect on spermatogenesis of the implantation of six rods containing levonorgestrel and three estrone rods was studied in seven volunteers aged 32–40, with normal pre-treatment spermiogram. None of the subjects achieved azoospermia. The lowest sperm count was below 1 million/ml in three subjects and below 12 million/ml in the other four. Plasma FSH and testosterone were severely depressed during the study, but LH was only transiently depressed for the first two months. Four subjects recovered pre-treatment sperm counts in spite of the FSH levels below 1.5 mIU/ml and testosterone levels below 1 ng/ml, which is contradictory to the current concept on hormonal regulation of spermatogenesis.     

Norplant contraceptive implants: rods versus capsules

Norplant contraceptive implants are silastic implants containing levonorgestrel. When placed subcutaneously in the medial aspect of the upper arm, they release low levels of levonorgestrel in a constant manner over an extended period of time. Comparative studies of two silastic rods versus six capsules containing levonorgestrel were studied in 250 subjects for 4,464 months of use. Only one pregnancy occurred during the study. Side effect patterns were similar in both groups; the major side effect being irregular uterine bleeding. The bleeding, however, was well tolerated by subjects in both groups and discontinuation rate was very low. The two-rod system offers the advantages of easier insertion technique and shorter insertion time as well as ease of removal as compared to the six-capsule system. Norplant contraceptive implants offer a highly effective means of contraception which is particularly suited for women who are concerned about failure and compliance with oral contraceptives. This type of contraception should become well accepted, not only in underdeveloped countries, but in developed countries as well.     

Fertility regulation in nursing women: VII. Influence of NORPLANT levonorgestrel implants upon lactation and infant growth

The objective of this study was to test the influence of NORPLANT implants upon lactation and infant growth. The results obtained during the first postpartum year are reported. One-hundred women were enrolled in the implant group. The control group was formed by 100 women who received a Copper T IUD. Treatments were administered at day 55 +/- 3. At admission all subjects were in exclusive breastfeeding with an adequate weight increase of the infant. No significant differences were found between the treated and control groups in the percentage of women in full nursing at different postpartum intervals, except for the 12th month postpartum where a lower percentage of cases from the NORPLANT group was in the full nursing category. No difference was found in the time of weaning. The infants showed a normal weight gain rate in both groups although the girls from the NORPLANT group showed a significantly lower daily weight increase during the 4th month than the girls from the IUD group. No pregnancies were diagnosed. No women asked for implant removal during the first year. No serious side effects related to treatment were detected. Bleeding irregularities were rare during breastfeeding which is in contrast with what occurs in non-nursing women treated with NORPLANT implants. Levonorgestrel concentrations found in milk were variable and individual values ranged from 23 to 311 pg/ml. The dose received by the infant can be estimated around 15 to 18 ng/Kg/day during the first month of treatment when the higher plasma values of levonorgestrel are observed. These levels is conjunction with the clinical observations reported here minimize the potential problems associated with levonorgestrel transference through maternal milk. Nevertheless, long-term studies are required to settle this matter and until more information is available, NORPLANT implant use in lactating women should be limited to cases who require a highly effective contraceptive method and where non-hormonal methods of similar effectiveness are contraindicated or unacceptable.     

Levonorgestrel plasma concentrations and hormone profiles after insertion and after one year of treatment with a levonorgestrel-IUD

Plasma concentrations of levonorgestrel, progesterone, estradiol, FSH and LH were measured in seven volunteers who had a levonorgestrel-releasing IUD inserted postmenstrually. Blood samples were collected twice weekly during a mean of 93 days immediately postmenstrually and during a mean of 41 days over the twelfth to fifteenth month of treatment. Patterns of bleeding were studied during the first year of treatment. The IUDs used were designed to release 25 micrograms/day of levonorgestrel. The mean +/- SD plasma concentration of levonorgestrel for all subjects during the first three months was 260 +/- 68 pg/ml, and 129 +/- 28 pg/ml after one year of treatment. During the initial period of blood sampling only two of the subjects ovulated, while only two did not ovulate after one year of treatment. Intermenstrual spotting occurred during the first sixty days of treatment. Three subjects developed amenorrhea at the end of the first year. All the subjects continued the use of the IUD and no pregnancies occurred.     

A five-year clinical trial of levonorgestrel silastic implants (Norplant™)

Silastic implants containing the progestin, levonorgestrel, were tested as a long-term contraceptive system in 101 women. During five full years of use, no pregnancies occurred. The 5-year continuation rate was 54%. Menstrual irregularities were the most frequent reason for termination of use but only during the first year. More than half of the terminations for this reason were in the first year. Some of the subjects elected to continue use of the implants beyond 5 years, allowing release rate data to be obtained through 6 years.From the second through the sixth year of use, the implants delivered a constant 30 micrograms per day of levonorgestrel to the subjects, and even after six years 57% of the original steroid content remained in the capsules.Return of fertility following removal was essentially immediate and not related to time of use. Medical reasons for removal were infrequent and no pattern was discernible.     

Progestin implants for female contraception

Four different implants, in the form of capsules or covered rods, that release one of the synthetic progestins levonorgestrel, etonogestrel, Nestorone, or Elcometrine and nomegestrol acetate were reviewed. Biocompatible polymers or copolymers of polydimethyl/polymethylvinyl-siloxanes or ethylvinylacetate are used to hold the steroid crystals and to control the rate of release. Once inserted under the skin, these implants release the corresponding steroid continuously over prolonged periods, a process that can be readily interrupted by implant removal. During long-term use of the implant, the released steroid circulates in blood at a fairly stable level. The physical characteristics of the implants, including drug contents and rate of release, serum levels of the progestin during use, and the duration of their effective life are described. Total steroid loads vary in the range of 50 mg to 216 mg; average release rates are in the range of 30-100 ug/day, and effective lives from 6 months to 7 years.     

Clinical chemistry in women treated with six levonorgestrel covered rods or with a copper IUD

A group of women treated with six levonorgestrel covered rods participated in a study on general chemistry and blood levels of selected hormones at treatment months 20 and 65. A comparable group of Copper T users served as control. Parameters analyzed were the SMA 12 chemistry profile, estradiol, testosterone, cortisol, T3, T4 and TSH. Samples from treated and control subjects were drawn within the same calendar period and were run simultaneously for the assay of each parameter. The values observed were within the normal limits. Significantly higher values of total protein and albumin and lower levels of estradiol and testosterone were found among implant users when compared to the control group. The results suggests little or no metabolic changes in users of six levonorgestrel covered rods which release a daily dose of approximately 105 micrograms.     

First year clinical experience with six levonorgestrel rods as subdermal contraception.

Previous clinical experience with six levonorgestrel subdermal capsules showed a very good contraceptive effectiveness and continuation rate, but with a high proportion of bleeding disturbances, particularly of increased bleeding. It was hypothesized that bleeding could be reduced by higher plasma levels of the steroid, using subdermal rods instead of capsules, as rods have been shown to have a release rate 3 or 4 times that of the capsules. Fifty volunteers were enrolled in a study of the clinical performance of 6 subdermal levonorgestrel rods. Results were compared with a previous experience with 100 volunteers who wore 6 levonorgestrel capsules for a year in the same clinic. Requirement for volunteers to enter the study were the same for capsules and rods. The proportion of women wearing 6 subdermal rods who had increased bleeding was about one half as for the women using 6 levonorgestrel capsules. On the other hand, women using rods had about twice the incidence of amenhorrea, and about four times more hypomenorrhea (4 days or less of bleeding in a 90-day period). There were no pregnancies among the rod users and the discontinuation rate for medical reasons was not higher than for capsule users in the same clinic.     

Clinical results with subcutaneous implants containing 3-keto desogestrel

Eight healthy women using one Silastic implant of 30 mm length filled with 3-keto desogestrel, the active metabolite of desogestrel, were studied for 36-664 days. The release rate of 3-keto desogestrel was quite constant and around 30 micrograms/day. No ovulations occurred. One woman was amenorrheic, while the others had different bleeding patterns, often with periods of spotting. No other side effects were recorded. The mean plasma levels of 3-keto desogestrel were 0.9 nmol/l after 1 month and 0.5 nmol/l after 12 months. 3-Keto desogestrel was less effective than testosterone, estradiol or levonorgestrel in displacing 3H-dihydrotestosterone from SHBG. It is concluded that contraception with 3-keto desogestrel delivered through an implant is a promising method for further investigation. With a single implant we found a duration of at least one year.