Alterations in endometrial stromal cell tissue factor protein and messenger ribonucleic acid expression in patients experiencing abnormal uterine bleeding while using Norplant-2 contraception.

A high incidence of irregular uterine bleeding is the primary patient complaint limiting the utility of long term, progestin-only contraceptive agents such as Norplant. The onset of hemorrhage requires both inadequate hemostasis and impaired vascular integrity. Thus, we first tested whether Norplant-associated endometrial bleeding was accompanied by altered expression of perivascular stromal cell tissue factor (TF), the primary initiator of hemostasis. Norplant effects on TF messenger ribonucleic acid (mRNA) and protein expression by endometrial stromal cells were assessed by in situ hybridization and immunohistochemical examination of endometrial biopsies obtained from normally cycling control women (n = 14) and from patients experiencing Norplant-induced abnormal uterine bleeding (n = 24). TF mRNA and protein expression was increased 150% in secretory vs. proliferative phase endometrial specimens. By contrast, endometrial TF mRNA and protein levels were reduced during 1-6 months of Norplant treatment by about 2-fold (P < 0.05 for protein) compared to the values for control secretory phase specimens. These changes were consistent with observations that patients on Norplant begin to bleed during this interval. Further reductions of TF mRNA and protein levels to 2- and 3-fold of those in secretory phase control specimens were observed in endometria obtained after 6-12 months of Norplant therapy (P < 0.05 and P < 0.01, respectively). A modest rebound in TF mRNA and protein expression was observed after 12 months of Norplant therapy, which occurred commensurate with reduced patient complaints of abnormal uterine bleeding. Pathologically enlarged venous sinusoids were ubiquitous in endometrial specimens obtained after Norplant therapy. The combination of fragile blood vessels and reduced TF expression may account for bleeding in patients receiving Norplant therapy.

Levonorgestrel contraceptive implants in female patients 14 to 21 years old.

OBJECTIVE: To determine which factors are associated with duration of use of a levonorgestrel implant (Norplant) for contraception in adolescents and young adults. DESIGN: We retrospectively studied 144 young women (14 to 21 years of age) who chose a levonorgestrel contraceptive implant at Mayo Clinic Rochester between April 1990 and December 1993. MATERIAL AND METHODS: The following information was obtained at the time of insertion of the implant and from any follow-up visits: demographics, prior contraceptive experiences, frequency and management of complications, complications noted at removal of the implant, and subsequent contraceptive choice. The duration of use was examined. RESULTS: Of the 144 young women who underwent insertion of a Norplant system, 75 telephoned or made a medical appointment because of implant-related side effects. During the follow-up period, 64 patients had the Norplant system removed. The Kaplan-Meier estimate of the probability of the Norplant system remaining in place for at least 12 months was 83 % and for at least 24 months was 63 %. Duration of Norplant use was not found to differ with respect to age, prior contraceptive use, or timing of insertion, but it was significantly shorter among those with a prior pregnancy than in those who had never been pregnant. CONCLUSION: These findings suggest that a group of young women who are likely to continue use of a contraceptive implant (with or without treatment for side effects) are those who have never been pregnant.

PIP: A retrospective study of 144 US women 14-21 years of age who requested and received the Norplant contraceptive implant system at the Mayo Clinic (Rochester, Minnesota) in 1990-93 analyzed the factors associated with duration of method use. Of the 124 women who reported past use of contraception, 94 (76%) had been pregnant at least once. The method most commonly used before Norplant was oral contraception (57%). The reasons for Norplant selection were its convenience (86%) and problems tolerating the pill (14%). Of the 130 Norplant users who either telephoned or made a clinic appointment after insertion, 60% reported side effects such as breakthrough bleeding, headache, and depression or mood swings. 64 women had the implants removed. The median duration of Norplant use was 29 months. The Kaplan-Meier estimate of the probability of the Norplant system remaining in place for at least 12 months was 83% and 63% for at least 24 months. Age, prior contraceptive use, and timing of insertion had no impact on duration of Norplant use. Multivariate analysis indicated that women with at least 1 prior pregnancy had a two-fold increased risk of Norplant removal compared to those who had never been pregnant. Larger studies are needed to identify additional factors associated with long-term use of injectable contraception among young women and to suggest interventions that would improve compliance with routine follow-up.

Effect of the progestogens, gestodene, 3-keto desogestrel, levonorgestrel, norethisterone and norgestimate on the oxidation of ethinyloestradiol and other substrates by human liver microsomes.

A number of different progestogens, levonorgestrel (LNG), norethisterone (NET), gestodene (GSD), desogestrel (DG) and norgestimate (NORG) are used in combination with the oestrogen ethinyloestradiol (EE2) in oral contraceptive steroid preparations. All the progestogens are acetylenic steroids and previous studies have indicated the potential of acetylenic steroids to cause mechanism-based or "suicide" inactivation of cytochrome P-450. We have compared the effects of the different progestogens on EE2 2-hydroxylation (a reaction catalyzed by enzymes from the P-450IIC, P-450IIIA and P-450IIE gene families) and also the oxidative metabolism of other drug substrates (cyclosporin, diazepam, tolbutamide) by human liver microsomes. On coincubation with EE2 as substrate, GSD, 3-keto desogestrel (3-KD, the active metabolite of desogestrel) and LNG produced some concentration-dependent inhibition of EE2 2-hydroxylation (maximum 32% inhibition at 100 microM 3-keto desogestrel). Ki values determined for GSD and 3-KD were 98.5 +/- 12.3 and 93.2 +/- 10.3 microM (mean +/- SD; n = 4), respectively. Preincubation of progestogens in a small volume (50 microliters) incubation for 30 min in the presence of an NADPH-generating system enhanced the inhibitory potential of all the steroids (at 100 microM, inhibition was for GSD 39%, 3-KD 46%, LNG 46%, NET 51% and NORG 43%). Inhibitory effects were therefore comparable and also similar to the macrolide antibiotic troleandomycin. The most marked inhibition seen was of diazepam N-demethylation and hydroxylation by GSD (71 and 57%, respectively) and 3-KD (62 and 50%, respectively). In preincubation studies involving cyclosporin as the substrate, the order of inhibitory potency was GSD greater than 3-KD greater than NET greater than LNG for production of both metabolite M17 and M21. The results of the study indicate that all the progestogens in common use have the propensity to inhibit a number of oxidative pathways but there is little evidence for one progestogen being more markedly inhibitory than others.

Levonorgestrel subdermal implants. Contraception on trial.

When they were introduced to the world market in the 1980s, levonorgestrel subdermal implants offered the promise of an exciting alternative to traditional hormonal contraception. They provide highly effective, long-acting protection from pregnancy, without the need for user compliance. Broad acceptability of the drug has been reported throughout the world. Recently, however, the implants have met with opposition. The drug is associated with a variety of adverse effects, and removal of implants can be problematic. Serious events have been reported in women using levonorgestrel subdermal implants, although causal relationships have not been demonstrated. Additionally, concerns have been raised over the potential for coercive use of the drug. Numerous law suits have been filed alleging serious problems with implants. As a result, the drug has received considerable negative media attention. Before the controversy over levonorgestrel subdermal implants erupted, contraceptive development had declined, resulting from limitations to profits and funding, legal threats, and changes in the insurance industry. The levonorgestrel subdermal implant experience may serve to accelerate this trend. While the introduction of levonorgestrel subdermal implants offered an alternative to the current array of medical contraception, its experience may serve to dampen future contraceptive development efforts. Costly litigation and much controversy involving the implants have acted to create disincentives to further research and development of new methods of medical contraception.

A risk-benefit assessment of the levonorgestrel-releasing intrauterine system.

The levonorgestrel-releasing intrauterine system (LNG-IUS), has been developed by Leiras Pharmaceuticals, Turku, Finland. It is a new systemic hormonal contraceptive that releases levonorgestrel 20 micrograms every 24 hours. The device provides fertility control comparable with that of female sterilisation, complete reversibility and convenience, and has an excellent tolerability record. The low dosage of levonorgestrel released by its unique delivery system ensures minimal hormone-related systemic adverse effects, which tend to be in the category of 'nuisance' rather than hazardous, and gradually diminish after the first few months of use. In some respects, the contraceptive characteristics of the LNG-IUS have over-shadowed a substantial range of noncontraceptive beneficial effects that are rarely seen with inert or copper-releasing intrauterine contraceptive devices (IUDs), and have important and positive gynaecological and public health implications. This applies particularly to the profound reduction in duration and quantity of menstrual bleeding, and alleviation of dysmenorrhoea, which are associated with the use of the device. Recent studies have shown that the LNG-IUS is effective in preventing endometrial proliferation associated with oral or transdermal estradiol therapy, and in inducing regression of endometrial hyperplasia. Further research is required to determine whether it has a role in regulating the growth of uterine fibroids, and preventing pelvic inflammatory disease. The unique unwanted noncontraceptive effects of the system, including possible development of functional ovarian cysts, and the relationship between menstrual bleeding pattern and ovarian function, also require better understanding, in order to offer appropriate patient counselling and maximise acceptability and continuation of use of the method.

PIP: The levonorgestrel-releasing intrauterine system (LNG-IUS) provides fertility control comparable to female sterilization, convenience, and complete reversibility. This method appears to combine the benefits of oral contraception and the IUD, while avoiding most of their side effects. The low level of LNG released (20 mcg every 24 hours) minimizes the systemic adverse effects associated with hormonal contraception. Unlike inert or copper IUDs, the LNG-IUS is associated with a profound reduction in the duration and quantity of menstrual bleeding and alleviates dysmenorrhea. Moreover, there is evidence that the LNG-IUS prevents the endometrial proliferation associated with estradiol therapy and induces regression of endometrial hyperplasia; its potential for regulating the growth of uterine fibroids and preventing pelvic inflammatory disease remains undetermined. Although large multicenter studies have not detected differences in cervical cytology or breast cancer incidence between copper IUD and LNG-IUS users, long-term epidemiological studies are needed to confirm this finding. Fundal positioning of the LNG-IUS is essential to ensure uniform exposure of the endometrium to the progestogen, prevent expulsion, and maximize efficacy. A promising future use for the LNG-IUS is in protecting the endometrium during postmenopausal hormone replacement therapy. Overall, the research suggests that the LNG-IUS comes close to meeting many of the requirements of an ideal contraceptive.

Impact of patient counseling on acceptance of the levonorgestrel implant contraceptive in the United Kingdom.

Patient counseling is an important aspect of family planning. Patient choice, compliance, and satisfaction with a contraceptive method depend heavily on the counseling experience. This is especially true in the United Kingdom where contraceptives are provided to patients at no direct cost to them. Women are therefore more likely to choose a contraceptive option based on perceived desirability as opposed to cost. We surveyed physicians from six family planning centers in the United Kingdom who have extensive experience with levonorgestrel contraceptive implants with respect to counseling issues and patient acceptability of levonorgestrel implants. The physicians reported on their experience with 521 women. They acknowledged the need for and importance of counseling, and these centers provided preinsertion counseling 100% of the time. Primary responsibility for counseling was handled by the physician who spent, on average, 19 minutes per patient discussing the advantages and risks of levonorgestrel implants. Physicians felt that the majority of women (82%) accepting levonorgestrel implants had a positive experience. The incidence of bleeding irregularities was consistent with that reported in clinical trials, and this did not substantially affect the postinsertion acceptability of the product. Effective counseling is no doubt responsible for the high level of patient acceptance of these side effects. In a review of the literature, we found counseling to be a significant factor in a woman's tolerance of contraceptive-induced bleeding irregularities, which are frequently experienced with levonorgestrel implants. The results of our survey support the literature findings.

Intracervical and fundal administration of levonorgestrel for contraception: endometrial thickness, patterns of bleeding, and persisting ovarian follicles.

OBJECTIVE(S): To study the prevalence of persisting ovarian follicles and to assess the endometrial changes and patterns of vaginal bleeding over 1 year of use of a 20 micrograms/24 h levonorgestrel-releasing intracervical contraceptive device. DESIGN: Prospective, randomized study. SETTING: Two family planning clinics in Helsinki, Finland. PATIENT(S): Women requesting intrauterine hormonal contraception. INTERVENTION(S): Insertion of a levonorgestrel-releasing intracervical contraceptive device into the cervical canal (group 1, n = 151) or fundally into the uterine cavity (group 2, n = 147) for contraception. MAIN OUTCOME MEASURE(S): Transvaginal ultrasonography of the ovaries and endometrium at insertion and 3, 6, and 12 months after insertion. Data on bleeding were collected using menstrual diary cards. RESULTS: Persisting ovarian follicles were found in < 8% of women. In both groups, the amount of endometrial tissue decreased significantly in 3 months. The incidence of amenorrhea during the 1st year was higher in the fundal insertion group. CONCLUSION(S): The number of persisting follicles was low. Follicles resolved within 6 to 8 weeks. No association was found between persisting follicles and problems of bleeding. Compared with intracervical insertion, fundal insertion resulted in more uniform endometrial suppression and fewer days of bleeding and spotting.

PIP: The prevalence of persisting ovarian follicles as well as endometrial changes and vaginal bleeding patterns associated with the levonorgestrel-releasing intracervical contraceptive device were investigated in a 12-month prospective study involving 398 women recruited from 2 family planning clinics in Helsinki, Finland. The device, which released 20 mcg of levonorgestrel per 24 hours, was inserted into the cervical canal in 151 women and fundally into the uterine cavity in the remaining 147 women. Transvaginal ultrasonography of the endometrium and ovaries was performed at insertion and at 3, 6, and 12 months post-insertion. The prevalence of persisting ovarian follicles was 6.5% at 3 months, 7.7% at 6 months, and 3.2% at 12 months, with no significant differences between the 2 study groups. All but 1 follicular structure resolved spontaneously within 6-8 weeks of follow-up. In both groups, endometrial tissue thickness decreased significantly by 3 months and remained thin for the duration of the study. The number of days of bleeding, documented through menstrual diaries, decreased slowly in the cervical group, from 4.0 in the first month to 2.0 in the sixth month and 1.0 in the 12th month; however, a very steep decrease occurred in the fundal insertion group, from 5.0 in the first month to 1.0 in the sixth month and 0.0 in the 12th month. 11% of women in the intracervical insertion group compared with 24% in the fundal insertion group experienced at least 1 continuous 90-day amenorrhea episode. There was no correlation between functional ovarian cysts and bleeding patterns. Although fundal insertion of an intracervical contraceptive device results in more uniform suppression of the endometrium, women who consider amenorrhea undesirable should have the device inserted cervically.

Immediate postpartum insertion of the norplant contraceptive device.

OBJECTIVE: To determine the safety and efficacy of Norplant (Wyeth-Ayerst Laboratories, Philadelphia, PA) insertion immediately postpartum. DESIGN: Prospective study of 14 women receiving Norplant immediately postpartum compared with controls (n = 6) having a bilateral tubal ligation. Subjects were followed for 3 months postpartum, and data were analyzed by analysis of variance and chi2. SETTING: Academic Health Sciences Center. PATIENTS: Female subjects 18 to 35 years old who had an uncomplicated term pregnancy, normal spontaneous vaginal delivery, and did not breast-feed. INTERVENTION: A brief interview, physical exam, and blood and urine samples were evaluated during a 12-week postpartum period. MAIN OUTCOME MEASURES: Major complaints, serum chemistry panels, hematologic and coagulative measures, serum E2, P, levonorgestrel, PRL, LH, FSH, and urinary estrone-3 conjugates and pregnanediol-3-glucuronide concentrations. RESULTS: Serum levonorgestrel peaked at approximately 2,000 pg/mL (6,400 pmol/L) during the 1st week after Norplant insertion, declining to approximately 250 pg/mL (800 pmol/L) by the 8th week. Significant differences between Norplant and control groups included bleeding irregularities, headaches, alopecia, and abdominal discomfort. Serum electrolytes, metabolic markers, and blood components were within normal limits. Serum E2, P, and urinary steriod biomarkers indicated that steroid secretion was suppressed severely in the Norplant group compared with controls who exhibited normal postpartum ovarian activity. CONCLUSION: Norplant inserted immediately postpartum appears to be a safe and effective method of contraception. However, the long-term hypoestrogenic state and contraceptive efficacy beyond the 3-month postpartum period as observed in this study are concerns that need further clinical evaluation.

PIP: During December 1992 to October 1994, in Texas, clinical researchers conducted a prospective case control study (15 cases receiving Norplant immediately postpartum vs. 6 controls undergoing bilateral tubal ligation immediately postpartum) to determine the safety and efficacy of inserting the contraceptive implant Norplant (6 capsules inserted subdermally, each containing 35 mg levonorgestrel) immediately postpartum. They followed the cases and the controls for three months. The study subjects were 18-35 years old, received prenatal care at one of the Department of Obstetrics and Gynecology's (Texas Tech University Health Sciences Center) community clinics, had an uncomplicated term pregnancy and normal spontaneous vaginal delivery, and did not breast feed. They tended to be poor. During the first week after Norplant insertion, serum levonorgestrel levels peaked at about 2000 pg/ml, then fell abruptly until about the eighth week to about 250 pg/ml. This lower levonorgestrel level concerned the researchers because it is just slightly higher than levels associated with pregnancy. They were also concerned about the possibility of Norplant inducing a hypoestrogenic state in postpartum women. The Norplant group was more likely than the tubal ligation group to experience irregular bleeding (p 0.01), headaches (p 0.01), hair loss (p 0.05), and abdominal discomfort (p 0.05). The various serum metabolic biomarkers, serum electrolytes, and blood components fell into the normal range in both groups. The serum estradiol, progesterone, and urinary steroid biomarkers suggested that the Norplant group experienced very suppressed steroid secretion throughout the three month study period, while the controls had normal postpartum ovarian activity. Thus, ovarian activity was absent in the Norplant group. These findings suggest that postpartum insertion of Norplant is safe and effective. Yet further clinical evaluation is needed to address concerns about the long-term hypoestrogenic state and contraceptive efficacy beyond the three month postpartum period.

The effects of two triphasic oral contraceptives on carbohydrate metabolism in women during 1 year of use.

Sixty-one women were randomly assigned to use one of two different triphasic oral contraceptives (OCs), for one year's time (Ortho Novum 777, Ortho Pharmaceutical Corp., Raritan, NJ, and Triphasil, Wyeth Laboratories, Philadelphia, PA), containing the progestins norethindrone and levonorgestrel, respectively. The carbohydrate metabolism was evaluated using the oral glucose tolerance test before OC use and at the end of the 12th month. Both plasma glucose and insulin levels were measured. The fasting glucose value in the norethindrone-containing OC group (777) was significantly lower at the 1-year testing. All other values were unchanged. These data demonstrate that the triphasic oral contraceptive preparations currently in use have minimal effects on carbohydrate metabolism.

PIP: Carbohydrate metabolism was investigated over 1-year period in new users of 2 different triphasic oral contraceptives (OCs)--Ortho Novum 777, which contains the progestin norethindrone, and Triphasil, in which levonorgestrel is the progestin. The 2 groups of women were similar in terms of age, parity, and weight. Carbohydrate metabolism was assessed through use of the oral glucose tolerance test before the onset of OC use and again after 12 months of use. In terms of plasma glucose results, only 1 value changed significantly during the study period; fasting glucose was lower than baseline in women taking the norethindrone triphasic OC. There was no significant change among users of either triphasic during the study period in plasma insulin levels. It is now believed that the elevations in birth plasma glucose and insulin levels recorded in earlier studies of OC users reflected the effects of the high dose of synthetic steroids used in these formulations, especially the progestins. The OCs that have been used since the 1980s indicate that low amounts of estrogen also improve carbohydrate metabolism, presumably by inhibiting the degradation of insulin. There are some indications that norgestrel tends to have a greater adverse effect on carbohydrate metabolism than norethindrone, perhaps accounting for the lowered fasting glucose in users of the norethindrone triphasic OC in this study. With norethindrone, the estrogen effect on carbohydrate metabolism predominates, but no significant fasting glucose change seems to occur when levonorgestrel counters the estrogen's improving effects on carbohydrates. Overall, these findings provide reassurance that the triphasic OCs currently in use have minimal effects on carbohydrate metabolism in addition to providing good cycle control and high rates of protection against pregnancy.

The effect of D-norgestrel, 30 micrograms, on the oral glucose tolerance test, including insulin levels, in Thai women.

The effect of D-norgestrel, 30 mug, on the oral glucose tolerance test was studied in 49 Thai women. There was a significant elevation of the blood glucose level at 60 minutes during the test in women who had taken D-norgestrel for 6 and 12 months. Insulin levels in the blood were significantly elevated over control levels in both groups of women at 90, 120, 150, and 180 minutes during the test. There was no difference in the results obtained at 6 months and 12 months. There was also no significant difference in the fasting blood glucose or insulin levels in the three groups of women. The results indicate that D-norestrel at a daily dose of 30 mug has an effect on carbohydrate metabolism in Thai women.

PIP: Oral glucose tolerance tests were performed on 49 Thai women to inve stigate the effect of d-norgestrel (30 mcg) on carbohydrate metabolism. At 60 minutes, women who had taken d-norgestrel for 6 and 12 months showed a significant increase in blood glucose levels (p less than .05). There was a significant increase in blood insulin levels at 90, 120, 150, and 180 minutes in both groups (p less than .05). However, fa sting blood glucose or insulin levels were not markedly different. It is concluded that d-norgestrel, at the dose studied, affects carbohydrat e metabolism in Thai women, and it is suggested that this may be a characteristic effect of 19-nor steroids.

Ovulatory dysfunction during continuous administration of low-dose levonorgestrel by subdermal implants.

OBJECTIVE: To study the endocrinologic profile of regularly menstruating users of levonorgestrel subdermal implants. DESIGN: Observational, prospective, case-controlled comparative study. SETTING: The Family Planning Clinic of PROFAMILIA, in Santo Domingo, Dominican Republic. PATIENTS, PARTICIPANTS: Thirty one regularly cycling Norplant users and 12 nonhormonal contraceptors who volunteered to participate. INTERVENTIONS: Norplant contraceptive implants were inserted in 31 subjects between 13 and 77 months before this study. MAIN OUTCOME MEASURES: Follicle-stimulating hormone, luteinizing hormone, estradiol (E2), and progesterone (P) were serially assayed for one menstrual cycle. RESULTS: Almost half of the cycles among Norplant users were anovulatory; all the rest (55%) had some form of dysfunction: diminished gonadotropin surge, luteal phase insufficiency (low P levels and shortened luteal phase), and E2 profiles different from normal controls. CONCLUSIONS: Anovulation is clearly one of the main mechanisms of action of Norplant, but even in presumptive ovulatory cycles, the dysfunctions described possibly contribute to the high contraceptive effectiveness of Norplant.

PIP: The study sought to examine the endocrinologic profile of regularly menstruating users of levonorgestrel subdermal implants. This observational, prospective, case-controlled, comparative study occurred at the Family Planning Clinic of PROFAMILIA in Santo Domingo, Dominican Republic. 31 subjects agreed to receive Norplant contraceptive implants between 13-77 months prior to this study and there were 12 nonhormonal contraceptors who also volunteered to participate. Follicle stimulating hormone, luteinizing hormone, estradiol (E2), and progesterone (P) were serially assayed for 1 menstrual cycle, and almost 1/2 of the cycles of norplant acceptors were anovulatory: the remainder (55%) had some form of dysfunction such as diminished gonadotropin surge, luteal phase insufficiency (low P levels and shortened luteal phase), and E2 profiles different from controls. Anovulation is clearly 1 of the main mechanisms of Norplant action, but even in presumptive ovulatory cycles, the dysfunctions described could have contributed to the high contraceptive effectiveness of Norplant.

Oral contraceptives: hormonal dose and effects on carbohydrate metabolism.

PIP: The progestational components of combined oral contraceptives induce a hyperinsulinemic response to glucose challenge, due either to a decrease in insulin receptor binding or to a postreceptor defect in cellular insulin action. This effect on glucose metabolism poses no heightened risk of diabetes in normal young women, but in women who have had previous gestational diabetes and in women over 35 there is increased risk of deteriorated glucose tolerance. Studies using a monophasic and triphasic ethinyl-estradiol/levonorgestrel combination for 6 months have shown that the triphasic preparation, which contains 40% less progestagen during 1 cycle, prevents the hyperinsulinemic response to glucose in both normal women and women with previous gestational diabetes. Since deteriorated glucose metabolism is associated with insulin-induced inhibition of lipolysis and synthesis of cholesterol and triglycerides in arterial tissue and ultimately with the development of arterial fatty streaks, it is advisable to use combined oral contraceptives with the lowest effective doses of estrogens and progestagens.^ieng

Recovery of fertility after use of the levonorgestrel 20 mcg/d or Copper T 380 Ag intrauterine device.

Following use of either the Levonorgestrel 20 mcg/day or the TCu 380 Ag IUD in a randomized comparative study, 110 women stopped contracepting to have planned pregnancies. Pregnancy rates and recovery of fertility have been assessed. Age at acceptance, duration of use, parity and intervals between last pregnancy and IUD insertion or removal were similar for both groups. Life table pregnancy rates at one year were higher than 90 per cent for both device groups; but because some women quickly changed their minds or had been at risk of pregnancy only a short time before the analysis date, only 60.9 percent had actually become pregnant. Median time to planned pregnancy was 3 months for the TCu 380 Ag group and 4 months for the Levonorgestrel 20 group. Neither duration of use nor age at insertion or age at termination affected the pregnancy rates significantly.

PIP: Following use of either the Levonorgestrel 20 mcg/day or the TCu 380 Ag IUD in a randomized comparative study, 110 women stopped contracepting to have planned pregnancies. Pregnancy rates and recovery of fertility have been assessed. Age at acceptance, duration of use, parity and intervals between last pregnancy and IUD insertion or removal were similar for both groups. Life table pregnancy rates at 1 year were higher than 90% for both device groups; but because some women quickly changed their minds or had been at risk of pregnancy only a short time before the analysis date, only 60.9% had actually become pregnant. Median time to planned pregnancy was 3 months for the TCu 380 Ag group and 4 months for the Levonorgestrel 20 group. Neither duration of use nor age at inserttion or age at termination affected the pregnancy rates significantly.

Norplant-2 rods: one year experience in Singapore.

Norplant-2 contraceptive implants consist of two silastic rods in which levonorgestrel has been incorporated with the polymer. This study describes our experience with 100 acceptors of the Norplant-2 rods in Singapore. No pregnancies occurred during the first year of use. Menstrual irregularities was the main complaint associated with the use of Norplant-2. However, the incidence of menstrual irregularities appeared to diminish with time and the continuation rate at the end of one year was 95.0 per cent. Thus, it appears that the Norplant-2 rod systems offer a highly effective, convenient means of contraception which should be well accepted in future.

Clinical performance of a levonorgestrel-releasing intracervical contraceptive device during the first two years of use.

One-hundred-and-ninety-eight women used a levonorgestrel-releasing intracervical contraceptive device (LNG-ICD) designed to release 20 micrograms levonorgestrel/day. Clinical performance during the first two years of LNG-ICD use was evaluated. A total of seven pregnancies occurred during the study period, all of them during the first year. Six pregnancies were after unnoticed expulsion of the device. One pregnancy occurred in an epileptic women using carbamazepine, with the LNG-ICD remaining in situ. Eighteen spontaneous expulsions occurred, 16 during the first year and 2 during the second year. Three pelvic infections were observed, all of them during the first year. Bleeding problems, hormonal side effects and other medical reasons were the most common side effects resulting in removal of the device. The continuation rate was 72.6 per cent after one year and 57.1 per cent after two years.

Norplant subdermal contraceptive system: experience in Taiwan.

From November 1988 to December 1994, a total of 567 female volunteers were enrolled in Norplant implant studies at the National Taiwan University Hospital. After a median follow-up of 29 months, only 3 of the 529 available cases became pregnant (a cumulative rate of 1.2 pregnancies per 100 users over 5 years). Chromosome analysis of 2 of the 3 abortuses revealed 46,XX/46,XX,inv(3) and 46,XX. Menstrual problems were the most common adverse effects and were also the main reason for discontinuation (65%, 108/166). The continuation rate was 90%, 78%, 70%, 61%, and 42% at the end of 1, 2, 3, 4, and 5 years after insertion, respectively. In the 21 patients who wished to become pregnant, fertility recurred soon after removal of the Norplant implants. The data suggested that the Norplant implants system is a highly effective, safe, and long-acting method of reversible contraception. It would be worthwhile to introduce this contraceptive system to Taiwan's family planning program.

PIP: Between November 1988 and December 1994 health providers at the National Taiwan University Hospital enrolled 567 women aged 17-47 in the Norplant implant studies that aimed to evaluate the benefits and side effects of Norplant as another contraceptive method choice. They followed the women for a median of 29 months. 38 cases were lost to follow-up. The 5-year contraceptive effectiveness rate was 98.8%. The 3 pregnancies (2 intrauterine and 1 ectopic) occurred during the 24th, 45th, and 47th months of use. None of the women who became pregnant weighed more than 70 kg. Two of the aborted fetuses had chromosomal abnormalities (46,XX/46,XX,inv(3) and 46,XX). 29.9% of the Norplant users had menstrual problems. Even though irregular bleeding occurred to 19.7% of Norplant users, hemoglobin levels increased after Norplant use (p 0.05). Triglycerides and total cholesterol levels decreased (p 0.05). None of the women developed thromboembolism. The Norplant continuation rate was 89.7% at 1 year, 78% at 2 years, 70% at 3 years, 61% at 4 years, and 42.4% at 5 years. The leading reason for implant removal was menstrual problems (108). The implants were removed during one sitting without x-ray or ultrasound identification in all 166 women who stopped using Norplant before 5 years and the 16 women who stopped using it at the end of 5 years. 78% of women who discontinued Norplant to become pregnant were pregnant within one year following removal. All their infants were normal. These findings suggest that Norplant is a safe, effective, and acceptable contraceptive method and that the family planning program should introduce Norplant to its contraceptive mix.

Effectiveness of Norplant implants among Thai women in Bangkok.

The purpose of the study was to evaluate the efficacy, acceptability, side effects and continuation rates of the implant system in Thai women. A five-year clinical study of 308 women receiving Norplant-6 implants in Bangkok was conducted. Acceptors' mean age was 29 years, and mean number of children was about two. More than half of the users (63%) finished primary school. The cumulative continuation rates for Norplant implants at first, second, third, fourth and fifth years were, respectively, 98%, 91%, 83%, 78% and 71%. Eight out of a total of eleven pregnancies occurred in the fourth and fifth year of use. The cumulative pregnancy rate was 1.1% for the third year, 2.0% for the fourth year and 4.2% for the fifth year. Desire for future pregnancy was the leading cause for termination of Norplant implants use. The five-year cumulative termination rate for planned pregnancy was 9.2%. Disruption of menstrual rhythm, particularly increased bleeding, was the other main reason for termination; however, the prevalence of menstrual irregularities appeared to diminish with time. The cumulative termination rate for menstrual irregularities in the fifth year of the study was 4.4%. The complaints of "other medical reasons" for removal of Norplant implants were acne, severe headache, and chloasma. The five-year cumulative termination rate for other personal reasons was 7.9%. These personal reasons were husband having vasectomy, husband objection and divorce. It can be seen from this five-year study that Norplant implants are well accepted by Thai women. However, the efficacy in preventing pregnancy was not acceptable during the fourth and fifth year of use in this study, which was different from results of other international studies.

PIP: Between June 1986 and December 1988, staff at a family planning clinic in greater Bangkok, Thailand, recruited 308 healthy women aged 18-45 for a clinical trial designed to evaluate the efficacy, acceptability, side effects, and continuation rates of the contraceptive implant system Norplant. Their average parity was 1.9 live births. The cumulative first-, second-, third-, fourth-, and fifth-year continuation rates stood at 97.6%, 90.7%, 82.9%, 77.9%, and 71%, respectively. During the first two years, no Norplant acceptor became pregnant. In the third year, however, the cumulative accidental pregnancy rate was 1.1% and increased to 2% in the fourth year and 4.2% in the fifth year. All accidental pregnancies were intrauterine. The major reason for Norplant removal was desire for pregnancy (5-year cumulative termination rate = 9.2%) followed by changes in menstruation patterns, particularly increased menstrual bleeding (4.4%). The prevalence of menstruation disorders decreased with time, however. For example, 64.8% of all users experienced an irregular menstrual cycle during the first 1-3 months of Norplant use. By 22-24 months of use, it had fallen to 54.9%, and to 39.5% by 58-60 months of use. The five-year cumulative termination rate for other personal reasons was 7.9%. These reasons included husband undergoing vasectomy, husband's objection to Norplant, and divorce. The relatively high continuation rates at the first and fifth year of use suggest that Thai women accepted Norplant well. The higher accidental pregnancy rates at four and five years of use than those of other international studies are troublesome, however.

Effect of Norplant implants on the pituitary-adrenal axis function and reserve capacity.

The present work investigated the effects of Norplant implants on the pituitary-adrenal function among 15 users of Norplant implants prior to and 6 months after insertion of the implants. Serum cortisol levels and their diurnal variations, ACTH and 24-h urinary 17-ketosteroids, ketogenic steroids, 17-hydroxy steroids, and creatinine, were measured. Also, a dynamic test (the 5-h Synacthen depot = ACTH stimulation test) was done before and 6 months after implants insertion. The 9 a.m. cortisol levels were blunted (within the normal ranges) while the 6 p.m. values were unaltered. The 24-h urinary ketogenic, hydroxy, and ketosteroids were also unchanged after Norplant implants use. The ACTH stimulation test showed a decreased adrenal response which was also within normal ranges. These data should raise the question related to suprarenal response to acute or prolonged stresses, such as surgical operations or shock in women using Norplant implants.

PIP: To ensure that Norplant contraceptive implants are not associated with a risk of pituitary-adrenal suppression, a series of laboratory tests were conducted in 15 women both before and 6 months after Norplant insertion. Comparisons of hormonal profiles before and after Norplant insertion revealed a significant drop in morning serum cortisol levels (404.33 +or- 84.07 nmol/l vs. 353.67 +or- 56.65 nmol/l, p 0.05), but no significant change in evening readings. The observed changes in morning cortisol values were still within the normal range. Serum ACTH values and 24-hour urinary 17-hydroxy steroids, 17-ketogenic steroids, and 17-ketosteroids were not different after insertion compared to baseline. Before Norplant insertion, injection of synthetic ACTH resulted in a 259.59 +or- 169.53% increase in the mean level of serum cortisol 5 hours later; 6 months after Norplant insertion, the percent rise above baseline was 165.85 +or- 91.64%. The significantly lower adrenal response among Norplant users (although still within normal limits) is presumably due to a local inhibition of the adrenal itself and not of the hypothalamic-pituitary axis. Although these findings suggest a minimal suppressive effect of prolonged microdose release of levonorgestrel from Norplant implants, the suprarenal response to acute or prolonged stresses (e.g., surgical operations or shock) in Norplant users requires investigation.

The effect of various steroids on corpus luteum function.

PIP: The effect of various steroids on corpus luteum function was investigated. The effect of d-norgestrel, R-5020, norethindrone, equilenin, megestrol acetate, estriol, and R-2323 was assessed by the effect on the progesterone secretion rate of the autotransplanted ovary of the ewe. Sheep with cervical ovarian autotransplants were used to facilitate infusion of the test compound directly into the arterial supply of the ovary and to allow progesterone secretion rates to be determined. Only 100mcg d-norgestrel/hour for 8 hours and 100 mcg R-5020/hour for 8 hours markedly suppressed progesterone ouput from the ovary.^ieng

Injectable depot contraceptives on d-norgestrel basis. I. Pharmacokinetic studies in dog and baboons.

PIP: The pharmacokinetics of 5 d-norgestrel 17beta-fatty acids with 6-16 carbon atoms, administered im, were studied in dogs and baboons. d-Norgestrel 17beta-undecylate and d-norgestrel 17beta-nonanoate most closely approached the optimum for uniform release over a 3-month period. In baboons, it was found that the bioavailability of d-norgestrel depended on the chain length of the esterified fatty acids, irrespective of the assay methods. Approximately 50% of d-norgestrel 17beta-nonanoate and 25% of d-norgestrel 17beta-undecylate is converted into de-norgestrel and fatty acid residue after release. After 3 months of treatment, both substances produced plasma levels of d-norgestrel which were equivalent to a daily d-norgestrel release of about 30 mcg. Since fluctuations in drug levels were less pronounced with d-norgestrel-C(11), it appears that this substance is suitable for study in humans.^ieng