Long-term depot-medroxyprogesterone acetate and bone mineral density.

The association between long-term use of depot-medroxyprogesterone acetate (DMPA) and bone mineral density (BMD) has been controversial, as seen in three case-control studies in New Zealand, Thailand, and the United Kingdom. In the present case-controlled study of BMD, a group of 67 Chinese women who had used DMPA from 5-15 years was compared with 218 women of the same age range who had not used any steroidal hormones. DMPA users were found to have a significantly lower BMD at lumbar vertebra (L2-4) (0.93 g/cm2), neck of femur (0.69 g/cm2), trochanter (0.59 g/cm2), and Ward's triangle (0.58 g/cm2), as compared with the control group, whose corresponding BMD values were 1.03 g/cm2, 0.83 g/cm2, 0.71 g/cm2, and 0.78 g/cm2, respectively (p < 0.001). The average percentage of bone loss per year was estimated to be 1.1% in L2-4, 2.3% in neck of femur, 2.4% in trochanter, and 3.5% in Ward's triangle. The percentage of bone loss in L2-4 was found to be more pronounced with age. This study provided information that the use of DMPA in a Chinese group for > 5 years in associated with bone loss, and a prospective study is needed to confirm these data, which are different from two case-control studies.

PIP: The effect of long-term use of depot medroxyprogesterone acetate (DMPA) on bone mineral density remains controversial. The present study compared bone mineral densities in 67 long-term (5 years or more) DMPA users recruited consecutively from the Hong Kong (China) Family Planning Association with those in 218 age-matched controls recruited from 8 family health service clinics in Hong Kong. Mean age was 42.8 years (range, 34-46 years) in the DMPA group and 40.0 years (range, 34-46 years) among controls. Body mass index, calcium intake, and smoking were similar in both groups. The median duration of DMPA use was 6 years (range, 5-15 years). Long-term DMPA users had significantly lower bone mineral densities than controls at the lumbar vertebra (0.93 vs. 1.03 g/sq. cm), neck of femur (0.69 vs. 0.83 g/sq. cm), trochanter (0.59 vs. 0.71 g/sq. cm), and Ward's triangle (0.58 vs. 0.78 g/sq. cm). The percentage of bone loss in L2-4 was more pronounced with increasing age. For each year of DMPA use, the decrease in bone mineral density was estimated to be 0.011 g/sq. cm (1.1%) in L2-4, 0.0193 g/sq. cm (2.3%) in the neck of femur, 0.0169 g/sq. cm (2.4%) in the trochanter, and 0.0277 g/sq. cm (3.5%) in Ward's triangle.

The effects of rifampin and rifabutin on the pharmacokinetics and pharmacodynamics of a combination oral contraceptive.

BACKGROUND: Rifampin (INN, rifampicin), a CYP34A inducer, results in significant interactions when coadministered with combination oral contraceptives that contain norethindrone (INN, norethisterone) and ethinyl estradiol (INN, ethinylestradiol). Little is known about the effects of rifabutin, a related rifamycin. OBJECTIVES AND METHODS: The relative effects of rifampin and rifabutin on the pharmacokinetics and pharmacodynamics of ethinyl estradiol and norethindrone were evaluated in a prospective, randomized, double-blinded crossover study in 12 premenopausal women who were on a stable oral contraceptive regimen that contained 35 microg ethinyl estradiol/1 mg norethindrone. Subjects were randomized to receive 14 days of rifampin or rifabutin from days 7 through 21 of their menstrual cycle. After a 1-month washout period (only the oral contraceptives were taken), subjects were crossed over to the other rifamycin. RESULTS: Rifampin significantly decreased the mean area under the plasma concentration-time curve from time 0 to 24 hours [AUC(0-24)] of ethinyl estradiol and the mean AUC(0-24) of norethindrone. Rifabutin significantly decreased the mean AUC(0-24) of ethinyl estradiol and the mean AUC(0-24) of norethindrone. The effect of rifampin was significantly greater than rifabutin on each AUC(0-24). Despite these changes, subjects did not ovulate (as determined by progesterone concentrations) during the cycle in which either rifamycin was administered. Levels of mean follicle-stimulating hormone increased 69% after rifampin. CONCLUSION: In this study, rifampin (600 mg daily) was a more significant inducer of ethinyl estradiol and norethindrone clearance than rifabutin (300 mg daily), but neither agent reversed the suppression of ovulation caused by oral contraceptives. The carefully monitored oral contraceptive administration and the limited exposure to rifamycins may restrict the application of this study to clinical situations.

PIP: The relative effects of rifampin and rifabutin (a related rifamycin) on the pharmacokinetics and pharmacodynamics of ethinyl estradiol (EE) and norethindrone were evaluated in a prospective, randomized, double-blinded crossover study in 12 premenopausal women who were on a stable oral contraceptive regimen that contained 35 mcg EE and 1 mg norethindrone. Subjects were randomized to receive 14 days of rifampin or rifabutin from days 7 through 21 of their menstrual cycle. After a 1-month washout period (only the oral contraceptives were taken), subjects were crossed over to the other rifamycin. Findings showed that rifampin significantly decreased the mean area under the plasma concentration-time curve from time 0 to 24 hours [AUC (0-24)] of EE and the mean AUC (0-24) of norethindrone. Rifabutin significantly decreased the mean AUC (0-24) of EE and the mean AUC (0-24) of norethindrone. The effect of rifampin was significantly greater than rifabutin on each AUC (0-24). Despite these changes, subjects did not ovulate (as determined by progesterone concentrations) during the cycle in which either rifamycin was administered. Levels of mean follicle-stimulating hormone increased 69% after rifampin. This study suggests that rifampin (600 mg daily) was a more important inducer of EE and norethindrone clearance than rifabutin, but none of these agents were able to reverse the suppression of ovulation done by oral contraceptives.

Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension): assessment of return of ovulation after three monthly injections in surgically sterile women.

The pharmacodynamic effects of medroxyprogesterone acetate (MPA) and estradiol cypionate (E2C) (MPA/E2C) (Lunelle Monthly Contraceptive Injection) on ovarian function were assessed through changes in serum progesterone concentrations. The data described here were obtained simultaneously with pharmacokinetic data presented in another article in this issue. Sixteen surgically sterile women with regular menstrual cycles were studied for one control cycle, three consecutive treatment months, and 3-5 months of follow-up. Suppression, followed by resumption of ovulation (the dynamic end point), was assessed by serum progesterone levels. Return of ovulation was presumptive based on progesterone concentrations > or = 4.7 ng/mL, as ultrasound was not used to determine the follicular/ovulatory status of these subjects. Luteal-like serum progesterone peaks were observed in all 16 women before drug administration, confirming the presence of ovulatory cycles. After the third monthly injection of MPA/E2C, progesterone concentrations were measured until demonstration of ovulation. Two women discontinued and three were lost to follow-up before this objective was achieved. Serum progesterone levels and, consequently, ovulation were suppressed beyond the entire dosing interval, indicated by the absence of any luteal-like progesterone peaks (serum progesterone concentrations did not exceed 1 ng/mL). The first normal ovulatory cycle, based on progesterone concentrations > or = 4.7 ng/mL, was observed in 11 women between days 63 and 112 after the third injection. Select medroxyprogesterone acetate parameters (i.e., area under the curve and minimum concentration) were correlated with return of ovulation. The correlation coefficients (r) were 0.757 and 0.492 for area under the curve and minimum concentration, respectively, indicating that return of ovulation is dependent, in part, on area under the curve and on the magnitude of the serum MPA trough level. In general, the higher the minimum concentration levels, the longer the time to return of ovulation. In conclusion, the return of ovulation, as confirmed by serum progesterone concentrations > or = 4.7 ng/mL, was observed as early as 63 days after the third and final monthly intramuscular injection of MPA/E2C, suggesting that consistent suppression of the hypothalamic-pituitary-ovarian axis is reversible after discontinuation of dosing.

PIP: This study assessed the pharmacodynamic effects of medroxyprogesterone acetate (MPA) and estradiol cypionate (E2C) (MPA/E2C) (Lunelle monthly contraceptive injection) through changes in serum progesterone concentrations. A total of 16 surgically sterile women with regular menstrual cycles were studied for one control cycle, three consecutive treatment months, and 3-5 months of follow-up. Serum progesterone levels and, consequently, ovulation were suppressed beyond the entire dosing interval, indicated by the absence of any luteal-like progesterone peaks. The first normal ovulatory cycle, based on progesterone concentrations of 4.7 ng/ml or higher, was noted in 11 women between days 63 and 112 after the third injection. Select MPA parameters were correlated with return of ovulation. The correlation coefficients were 0.757 and 0.492 for area under the curve and minimum concentration, respectively, indicating that return of ovulation is dependent, in part, on area under the curve and on the magnitude of the serum MPA trough level. Generally, the higher the minimum concentration levels, the longer the time to return of ovulation. This study concluded that the return of ovulation, as confirmed by serum progesterone concentrations of 4.7 ng/ml or higher, was observed as early as 63 days after the third and final monthly intramuscular injection of MPA/E2C. This indicates that consistent suppression of the hypothalamic-pituitary-ovarian axis is reversible after discontinuation of dosing.

Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension): effects of body weight and injection sites on pharmacokinetics.

A new contraceptive option, medroxyprogesterone acetate (MPA) and estradiol cypionate (E2C) (MPA/E2C, Lunelle Monthly Contraceptive Injection), will soon be available for women in the US. This article reports the results of a US trial that assessed the effects of body weight and injection site on the pharmacokinetics of MPA, the progestin mediating contraceptive efficacy. This assessment was part of a nonrandomized, open-label, multicenter US study in healthy women receiving a monthly injection of MPA/E2C for 60 weeks. A total of 77 women (aged 18-47 years) at four centers participated in the pharmacokinetics assessment during the sixth or the seventh injection. For determination of serum MPA concentration-time profiles, blood samples were collected before the sixth and seventh injections (day 0) and on days 3, 7, 14, 21, and 28 after the sixth and seventh monthly administrations. For effects of injection site, MPA pharmacokinetics were compared at injection sites of the arm, hip, and leg. The pharmacokinetics of MPA, determined at the sixth and seventh injection, were not significantly affected by injection sites. The mean area under the curve (AUC0-28), however, was different between the arm and the leg injection sites; the difference was < 20%. More important, the average MPA trough concentrations (Cmin) at the fifth and sixth monthly injections were similar (range 0.42-0.51 ng/mL) for the three injection sites and well above the threshold levels of 0.10-0.20 ng/mL required to suppress ovulation. For effects of body mass index (BMI) on pharmacokinetics, women were stratified into three groups: thin/normal (BMI 18-28, n = 48), obese (BMI 29-38, n = 23), and highly obese (BMI > 38, n = 6). There were no significant differences in the pharmacokinetics of MPA among the three BMI categories. The only significant difference (p = 0.0387) was the AUC0-28 between BMI 18-28 and BMI 29-38. Because of the small sample size in the highly obese group, a reanalysis was performed by pooling subjects of the obese and highly obese groups. Results of the pooled statistical analysis remained the same. In summary, these results suggest that minor differences observed in the MPA pharmacokinetics--whether due to injection site or body weight or both--have no impact on the contraceptive efficacy of MPA/E2C, as trough concentrations (Cmin) are well above the threshold levels required to suppress ovulation. No dose adjustment is necessary based on body weight or injection site.

PIP: A nonrandomized, open-label, multicenter study assessed the effects of body weight and injection site on the pharmacokinetics of medroxyprogesterone acetate (MPA) and its progestin medicating contraceptive efficacy among 77 healthy, fertile women aged 18-47 years. For determination of serum MPA concentration-time profiles, blood samples were collected before the 6th and 7th injections (day 0) and on days 3, 7, 14, 21, and 28 after the 6th and 7th monthly administrations. For injection site effects, MPA pharmacokinetics were compared at the injection sites of the arm, hip, and leg; there was no significant finding. For effects of body mass, no significant differences were noticed in the pharmacokinetics of MPA among the 3 body mass indices (thin/normal, obese, highly obese). However, a difference (p = 0.0387) was found between normal and obese women (20%). The findings suggest that minor differences observed in MPA pharmacokinetics have no impact on the contraceptive efficacy of MPA/E2C, may it be due to injection sites or body weight, since trough concentrations are well above the threshold levels required to suppress ovulation.

Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension): steady-state pharmacokinetics of MPA and E2 in surgically sterile women.

The steady-state pharmacokinetics and pharmacodynamics of medroxyprogesterone acetate (MPA) and estradiol (E2, released from E2C by esterase enzymes) were characterized after administration to surgically sterile women. This report describes the pharmacokinetics of this multiple-dose and open-labeled study (pharmacodynamics are reported in a subsequent article in this issue). Women with regular menstrual cycles were studied for one control cycle, 3 consecutive treatment months, and 3-5 months of follow-up. Blood samples were drawn before each monthly dose and at specified time points after the third monthly injection. A total of 16 women were enrolled, 14 of whom completed the study. These 14 women (13 white, one black) ranged in age from 28 to 43.4 years, in body weight from 47.6 to 68.9 kg, and in height from 150 to 175 cm. Mean serum MPA concentrations peaked in the first week after administration of MPA/E2C (Lunelle Monthly Contraceptive Injection). The mean MPA Cmax and AUC0-t(last) were 1.25 ng/mL and 32.13 ng.day/mL, respectively. Serum MPA concentrations declined with a mean terminal half-life of 14.7 days, indicating that absorption from the injection site is prolonged after administration of MPA/E2C. The time for MPA concentrations to fall below the lower limit of quantitation (i.e., < 10 pg/mL) after the third injection ranged from 63 to 84 days. The average MPA trough (Cmin' day 28) concentrations for the three consecutive monthly injections ranged from 0.44 to 0.47 pg/mL, indicating that steady-state conditions were achieved after the first injection. The MPA Cmin values were well above threshold levels required to suppress ovulation throughout the injection interval. Absorption of E2 from the injection site was also prolonged after injection of MPA/E2C. Mean concentrations of E2 peaked at approximately 2 days after the third injection, and the average Cmax was 247 pg/mL. Serum E2 levels declined with a terminal half-life of approximately 8 days; E2 levels returned to baseline (typically, approximately 100 pg/mL) by 14 days after each injection. The average trough (Cmin' day 28) levels for E2 ranged from 40 to 55 pg/mL. The results of this study demonstrate that steady-state conditions are achieved after the first injection of MPA/E2C; no further MPA or E2 accumulation occurs beyond the first injection. Furthermore, the E2 peak observed after injection of MPA/E2C is similar to the nontreated preovulatory E2 range and returns to baseline levels by approximately 14 days after injection.

PIP: This paper characterized the pharmacokinetics and pharmacodynamics of medroxyprogesterone acetate (MPA) and estradiol cypionate (E2C) in 14 healthy, surgically sterile women. These women ranged in age from 28 to 43.4 years, in body weight from 47.6 to 68.9 kg, and in height from 150 to 175 cm. The results of this study demonstrate that steady-state conditions are achieved after the first injection of MPA/E2C; no further MPA or E2C accumulation occurs beyond the first injection. Moreover, the E2 peak observed after injection of MPA/E2C is similar to the nontreated preovulatory E2 range and returns to baseline levels by approximately 14 days after insertion.

Sex hormone binding globulin and free levonorgestrel index in the first week after insertion of Norplant implants.

Levonorgestrel has an inhibitory effect on sex hormone binding globulin (SHBG). This decrease in SHBG leads to an increase in the free levonorgestrel index (FLI), which has a stronger biological effect. The interaction between serum levels of levonorgestrel and SHBG in long-term users of Norplant implants has been described. This study was designed to understand the same interaction immediately after the insertion of the implants, in a group of 16 women, sampled at 0 and 6 h and at 1, 3, and 7 days after Norplant implant insertion. Peak serum levonorgestrel levels were achieved at 24 h after insertion, remaining stable on day 3 and decreasing by > 10% by day 7. SHBG did not change during the first 24 h, but decreased by 19% and 60% on days 3 and 7, respectively. FLI more than doubled from day 1 to day 7 after insertion. The large decrease in SHBG and doubling of FLI is not followed by a similar reduction in levonorgestrel, which is hard to explain without an increase in the release rate of the steroid from the capsule.

PIP: It has been documented that levonorgestrel (LNG) administration by any route induces a significant reduction in circulating levels of sex hormone binding globulin (SHBG), which, in turn, leads to an increase in the free LNG index (FLI). A previous study found a pronounced reduction in SHBG levels as early as 7 days after insertion of the LNG-releasing Norplant contraceptive implants. The present study investigated the same interaction 1-7 days after Norplant insertion in 16 women recruited from a family planning clinic in Santo Domingo, Dominican Republic. Mean SHBG level at insertion was 75.9 nmol/l and was essentially unchanged 24 hours later. On postinsertion day 3, however, a 19% reduction over baseline was recorded. This decrease in SHBG was even more marked between days 3 and 7. By day 7, the mean SHBG serum level was only 40% of that found at the time of implant insertion. 6 hours after implant insertion, LNG levels were already above 700 pg/ml and peaked at over 1000 pg/ml at 24 hours, remained stable at this level until day 3, and then showed a moderate and nonsignificant decline of about 10%. The FLI was 5.1 at 24 hours postinsertion, remained at this level until day 3, and reached 11.9 by day 7. The lack of a significant reduction in LNG between postinsertion days 1 and 7 was unexpected given the 60% drop in SHBG and the doubling in the FLI. Two possible explanations for this finding are an increase in the amount of LNG entering the circulation or a large cross-reaction of the LNG assay with LNG metabolites in serum.

Experience of Thai women in Bangkok with Norplant-2 implants.

A prospective study of the Norplant-2 contraceptive subdermal implant system was conducted in Bangkok, Thailand. The objective of the study was to evaluate the efficacy, adverse effects, and overall acceptability of Norplant-2 implants. A total of 140 women were enrolled in a 3-year clinical trial. The mean age was 29 years. Of all the acceptors, 70% had completed primary school. The continuation rates at years 1, 2, and 3 were, respectively, 94%, 89%, and 83%. No accidental pregnancies occurred throughout the 3 years of use in this study. Personal reasons were the leading cause for termination of Norplant-2 implant use. The 3-year cumulative termination rate for personal reasons was 7.2%. These personal reasons were divorce, husband having vasectomy, and moving away from the study area. The other leading cause for termination was medical reasons; acne, headache, and pain at the implant site were the complaints. The termination rate for medical reasons in year 3 of the study was 4.6%. Prolonged menstrual flow was the other main reason for termination. The 3-year cumulative termination rate for menstrual irregularities was 3.8%. In this study, the cumulative termination for planned pregnancy at the end of the year 3 was only 1.6%. The incidence of difficult removals was 8%. Breakage of the rods on removal was encountered in the majority of these cases. The study findings presented suggest that the Norplant-2 implants are highly effective with high continuation rates. The Norplant-2 system could become another choice of long acting reversible contraception for Thai women.

PIP: Since 1986, Thailand's National Family Planning Program has included the Norplant 6-capsule implant system. The present paper reports the results of a 3-year Phase III clinical trial of the newly developed 2-rod system (Norplant-2). A total of 140 women (mean age, 29 years), in Bangkok, were enrolled and 103 women completed 3 years of method use. The continuation rates at 1, 2, and 3 years were 93.9%, 89.2%, and 82.8%, respectively. There were no accidental pregnancies during the 3-year study period. The 3-year cumulative termination rate was 7.2% for personal reasons (e.g., divorce, husband underwent vasectomy), 4.6% for medical reasons (e.g., acne, headache, pain at the implant site), and 3.8% for menstrual irregularities. A total of 125 acceptors underwent Norplant removal either during or at the end of the study period. The incidence of difficult removals was 8%. In most of these cases, the difficulty involved rod breakage. The average time required for removal was 3.4 minutes. These findings indicate that Norplant-2 is a safe, effective, acceptable contraceptive method appropriate for inclusion in Thailand's family planning program. The potential for fragmentation of the rods during removal requires careful monitoring, however.

A 2-year comparative study of endometrial histology and cervical cytology of contraceptive implant users in Birmingham, UK.

The objectives of this study were to evaluate the endometrial histology and cervical cytology of users of two contraceptive implants releasing etonogestrel/3-keto-desogestrel (Implanon) and levonorgestrel (Norplant) in West Midlands (UK) users. A 2-year prospective randomized design was used to study 60 implant users. Endometrial histology and cervical cytology were compared before insertion and after 12 and 24 months. At the end of 12 months, the majority of samples were inactive/weakly proliferative in both groups. At the end of 24 months, this remained unchanged in the Implanon group whereas the pattern was more diverse in the Norplant group. Endometrial thickness was significantly reduced in both groups during treatment. Cervical cytology remained unchanged. It is concluded that, after 2 years, there was no evidence of an increasing risk of endometrial hyperplasia, endometrial carcinoma, cervical intra-epithelial neoplasia or cervical carcinoma in either of the two groups of implant users.

PIP: Changes in endometrial histology and cervical cytology related to use of two contraceptive implants were investigated in a 2-year prospective study conducted at Birmingham (UK) Women's Hospital. 60 women with regular menstrual cycles were randomly assigned to receive either Implanon (etonogestrel/3-keto-desogestrel) or Norplant (levonorgestrel). After 12 months of implant use, most endometrial samples in both groups were inactive or only weakly proliferative. After 24 months, this pattern remained unchanged in the Implanon group. It was more diverse, however, in the Norplant group, where there was evidence of proliferative-phase endometrium. Endometrial thickness, assessed quarterly by transvaginal ultrasound scans, was significantly reduced in users of both implants. Cervical cytology remained unchanged from baseline to 24 months. These findings suggest that users of both implant systems are not at increased risk of endometrial hyperplasia, endometrial carcinoma, cervical intra-epithelial neoplasia, or cervical carcinoma.

Precise measurements of intrauterine vascular structures at hysteroscopy in menorrhagia and during Norplant use.

Using currently available equipment for panoramic hysteroscopy, the size of images viewed cannot be accurately judged because of the magnifying and distorting effects of the objective lens. This study has demonstrated that magnification by the hysteroscope lens can alter the apparent size of images by up to 27%. An additional effect of lens distortion can alter the apparent size of images viewed by up to 28%, depending on the position of the image in the field of view. These effects are independent and may be additive. Thus, the apparent size of intrauterine structures at hysteroscopy may bear little resemblance to their actual size. Image-correction methods are described which reduce the effects of image magnification on the apparent size of an object viewed through the hysteroscope to 7%, and the effect of distortion to 3 %. This technique can greatly improve the accuracy of measurement at hysteroscopy, and has been utilized in this study for the precise measurement of superficial endometrial vascular diameter (mean+/-SEM) in 34 Norplant users (120+/-11.6 microm) and 20 women with spontaneous menorrhagia (74+/-7.2 microm). It has also confirmed the presence of scattered dilated vessels (up to 777 microm in diameter) on the endometrial surface in some Norplant users.

PIP: As a result of the magnification and distortion caused by the fish-eye lens of the panoramic hysteroscope, the size of images cannot be measured accurately. Magnification can alter the apparent size of images by up to 27%, while lens distortion can produce an alteration of up to 28%. These effects are independent and may be additive. The present study applied a new technique for measuring the diameter of intrauterine structures at hysteroscopy to measurement of the superficial vasculature in 34 Norplant users recruited from a family planning clinic in London, England, and in 20 controls diagnosed at the hysteroscopy clinic with ovulatory dysfunctional uterine bleeding. This technique involved advancement of biopsy forceps into the field of view, use of a grid of known internal size, and computer-assisted transformation of the curved image into a flattened one. The mean diameter of superficial dilated vessels in Norplant users (120 mcm) exceeded that in women with menorrhagia (74 mcm). Scattered dilated vessels up to 777 mcm in diameter were observed on the endometrial surface in some Norplant users. The small endometrial polyps observed in Norplant users appeared to have a single fine vessel in the pedicle and were transparent. The image correction technique reduced the effect of image magnification on the apparent size of an object viewed through the hysteroscope to 7% and the effect of distortion to 3%.

Effect of oral contraceptive progestins on serum copper concentration.

OBJECTIVES: Recent epidemiologic studies have shown an increased mortality from cardiovascular diseases in people with higher serum copper levels. Even though higher serum copper concentration in women using oral contraceptives is well known, there is still uncertainty about the influence of newer progestin compounds in oral contraceptives on serum copper concentration. This issue is of particular interest in the light of recent findings of an increased risk of venous thromboembolism in users of oral contraceptives containing newer progestins like desogestrel compared to users of other oral contraceptives. DESIGN: Cross-sectional epidemiologic study. Examinations included a detailed questionnaire on medical history and lifestyle factors, a seven day food record, and blood samples. SETTING: National health and nutrition survey among healthy people living in private homes in West Germany in 1987-1988. SUBJECTS: Nonpregnant and nonlactating women aged 18-44 y (n = 610). RESULTS: Overall, the use of oral contraceptives was positively associated with serum copper concentration in by bi- and multivariable linear regression models with log-transformed values of serum copper concentration as dependend variable and oral contraceptive preparations and potential confounding variables as independent variables. Serum copper concentration in women using oral contraceptives varied more strongly by different progestin compounds than by estrogen contents. The highest increase of serum copper was seen in women using oral contraceptives containing antiandrogen progestins (55%; 95% CI: 37-76%), followed by desogestrel (46%; 95% CI: 36-56%), norethisteron/lynestrenol (42%; 95% CI: 29-57%), and levonorgestrel (34%; 95% CI: 24-45%). CONCLUSION: While elevated serum copper concentration was found in users of all types of oral contraceptives, elevation was more pronounced among women taking oral contraceptives with antiandrogen effective progestins like antiandrogens or third generation oral contraceptives containing desogestrel. Further investigation is required to shed light on the possible role of high serum copper concentration in increasing cardiovascular or thrombotic risk of women using oral contraceptives.

PIP: High serum copper concentration--a well-known effect of oral contraceptive (OC) use--has been linked to increased mortality from cardiovascular disease. The influence of OCs containing newer progestins has not been investigated, however. This concern was addressed in a 1987-88 cross-sectional epidemiologic study of 610 nonpregnant, nonlactating West German women 18-44 years of age. 195 women (32.1%) were current OC users, but only 152 of these women were able to cite the name of the formulation they were taking. In 70% of cases, the OC contained less than 45 mcg of ethylestradiol (median dose, 32.4 mcg). The most common progestin components were desogestrel (41%) and levonorgestrel (30%). Mean serum copper concentration was higher among users of all types of OCs than among non-users, but this concentration varied more strongly according to the OC's progestin compound than its estrogen content. The greatest increase in serum copper (55% compared with non-users) was recorded in users of OCs containing anti-androgen progestins, followed by desogestrel (46%), norethisterone/lynestrenol (42%), and levonorgestrel (34%). The increase in serum copper was more pronounced in women taking OCs containing 45 mcg or less of ethylestradiol than in users of OCs with a high estrogen dose. In the regression models, the different progestin compounds alone explained 28% of the total variance in serum copper concentration. Further investigation of OC-induced increases in serum copper concentration and their impact on cardiovascular risk are warranted.

Effect of two oral contraceptives containing ethinyl estradiol and gestodene or norgestimate on different lipid and lipoprotein parameters.

The effect of a triphasic oral contraceptive containing ethinyl estradiol and gestodene (EE/GSD) on various lipid and lipoprotein parameters was compared with that of a monophasic formulation containing 35 micrograms ethinyl estradiol and 250 micrograms norgestimate (EE/NGM). Blood samples were collected from 46 women on days 2, 11, and 21 of the preceding control cycle and of the third, sixth, and twelfth treatment cycles. There was no significant difference between formulations with regard to the influence on any measured parameter. As compared with controls, a significant increase was observed in the plasma levels of total triglycerides (24-78%), total phospholipids (7-20%), very low density lipoprotein (VLDL) triglycerides (61-76%), VLDL-phospholipids (14-60%), low density lipoprotein (LDL) triglycerides (8-35%), LDL-phospholipids (28-30%), high density lipoprotein (HDL) cholesterol (8-16%), HDL 3-cholesterol (11-20%), HDL-triglycerides (17-66%), HDL-phospholipids, HDL 3-phospholipids (7-11%), apolipoprotein (apo) A-I (5-20%) and apo A-II (10-40%) during treatment with both formulations. In contrast, the LDL-cholesterol levels were significantly decreased. These changes in lipid metabolism appear to reflect a predominance of the effect of the estrogen component. The results indicate that both low dose oral contraceptives containing different progestins and different amounts of EE do not exert a deleterious effect on lipoprotein metabolism, as high HDL-cholesterol and low LDL-cholesterol levels are known as low risk factors of cardiovascular disease. In contrast to endogenous hypertriglyceridemia, an EE-induced rise in triglyceride levels does not appear to increase cardiovascular risk if LDL is not increased.

PIP: Oral contraceptives (OCs) that contain a progestogen with high androgenic activity have been shown to have an atherogenic effect on lipid and lipoprotein metabolism. The present study compared the effect of a triphasic OC containing ethinyl estradiol and gestodene on selected lipid and lipoprotein parameters with that of a monophasic OC containing 35 mcg of ethinyl estradiol and 250 mcg of norgestimate. 46 healthy volunteers from Frankfurt, Germany, were enrolled and randomly assigned to receive one of the two OCs. Serum samples were collected on days 2, 11, and 21 of the control cycle and treatment cycles 3, 6, and 12. No significant differences between formulations were observed for any of the measured parameters. Significant increases were recorded during OC use in plasma levels of total triglycerides (24-78%), total phospholipids (7-20%), very low density lipoprotein (VLDL) triglycerides (61-76%), VLDL phospholipids (14-60%), low density lipoprotein (LDL) triglycerides (8-35%), LDL phospholipids (28-30%), high density lipoprotein (HDL) cholesterol (8-16%), HDL 3-cholesterol (11-20%), HDL triglycerides (17-66%), HDL phospholipids (7-11%), apolipoprotein (apo) A-I (5-20%), and apo A-II (10-40%). In contrast, LDL-cholesterol levels were significantly decreased during treatment with both formulations. These changes appear to reflect a predominance of the effect of the estrogen component.

Introduction of cyclofem once-a-month injectable contraceptive in Mexico.

A large introductory study of Cyclofem, a once-a-month injectable contraceptive, was conducted in three Mexican provinces. A total of 3457 healthy women participated: 640 women from rural areas (community-based component) and 2817 women from urban and suburban areas (health center-based component). A total of 20,316 women-months of treatment experience were accumulated during a one year period. Cyclofem proved its use-effectiveness (pregnancy rate of 0.03%) and its safety under routine service conditions of family planning facilities in Mexico. The overall life table continuation rate at 1 year was 26.1%. Higher continuation rates were observed in the community-based component (36.6%) as compared to the health center component (23.7%). The most common reason for method discontinuation was change of address. Only 15% of the discontinuations were attributable to the injectable contraceptive method, with the overall 1 year discontinuation rate for bleeding problems (including amenorrhea) was < 11%. These observations underscore the importance of appropriate counseling and follow-up measures, providing convenient access to repeat injections, and other service delivery issues related to continuation of Cyclofem. The results of this trial have once again demonstrated that Cyclofem is a highly effective method with an acceptable side effect profile. In addition, the study provided the elements for its approval by local health authorities and its inclusion into the Ministry of Health Family Planning Program.

PIP: The effectiveness and continuation rates associated with the once-a-month injectable contraceptive Cyclofem were investigated in an introductory trial conducted in three Mexican provinces (Sinaloa, Guanajuato, and Veracruz). Cyclofem contains 25 mg of medroxyprogesterone acetate and 5 mg of estradiol cypionate. A total of 3457 women (640 women from rural communities and 2817 from urban and suburban family planning centers) were enrolled and 20,316 woman-months of treatment experience were accumulated during the 12-month study period. The mean age of study participants was 23.6 years; 70% had previously used at least one contraceptive method. There was only one pregnancy (rate, 0.03%). The overall life-table continuation rate at 1 year was 26.1%, but this rate was higher in the community-based group (36.9%) than in the health center group (22.4%). This discrepancy is presumed to reflect the greater access of clinic clients to other contraception options. Continuation was highest among women 30-34 years of age, those with low levels of education, women with five or more children, and those who did not want more children. Only 14% of discontinuations were method-related. The 1-year discontinuation rate for bleeding problems, including amenorrhea, was 10.2%. These findings indicate Cyclofem is a safe, effective method appropriate for inclusion in Mexico's Ministry of Health Family Planning Program.

Bias versus causality: interpreting recent evidence of oral contraceptive studies.

Late in 1995 and early 1996, 4 epidemiologic studies were published that resulted in a crude mean weighted relative risk of approximately 2 when third-generation oral contraceptives were compared with second-generation oral contraceptives as risk factors for venous thromboembolism. This article reviews empirical evidence on bias or systematic error that may have influenced the estimates of association. The Bradford-Hill criteria to distinguish causality from an observed association were used to consider whether third-generation oral contraceptives cause an apparent excess in the occurrence of venous thromboembolism. Bias is more likely than a causal relationship to explain the associations observed for venous thromboembolism. For myocardial infarction, bias may mask the full benefit of third-generation oral contraceptives. For stroke, the question of causality is moot because statistically significant differences between third- and second-generation products have not been detected. The clinical importance and the public health significance of any differences among the various products with respect to adverse cardiovascular outcomes are trivial and undetectable because of the extremely low incidence of those disorders among users of oral contraceptives. The oral contraceptive pill is 99.9% effective when used correctly. All oral contraceptives on the market are safe and getting safer.

PIP: Four epidemiologic studies published in 1995-96 reported a crude mean weighted relative risk for venous thromboembolism of approximately 2 when third-generation oral contraceptives (OCs) were compared with second-generation formulations. This paper considers empirical evidence of bias or systematic error that may have influenced the estimates of association. Specifically, it asks 1) whether an odds ratio of 2 for venous thromboembolism in users of third- compared with second-generation OCs is accurate or has been spuriously increased by bias and 2) whether causality can be assumed from the observed association reflected in a relative risk of 2. Bias--particularly healthy user, prescription, and referral bias--is more likely than a causal association to explain the associations observed for venous thromboembolism. For myocardial infarction, bias may mask the full benefit of third-generation OCs. For stroke, the question of causality is moot because statistically significant differences between third- and second-generation OCs have not been detected. Moreover, the clinical importance and public health significance of any differences between these OCs in terms of adverse cardiovascular outcomes are trivial because of the extremely low incidence of these disorders among OC users.

Effects on hemostatic variables of desogestrel- and gestodene-containing oral contraceptives in comparison with levonorgestrel-containing oral contraceptives: a review.

In some studies third-generation oral contraceptives have been reported to be associated with a higher risk of venous thromboembolism than are second-generation oral contraceptives, whereas recent, more refined studies have not confirmed this. The reasons for the alleged differences are under discussion, and differential effects on hemostasis have been proposed. Eighteen studies comparing second- and third-generation oral contraceptives with respect to their effects on hemostasis were analyzed. Significant changes from baseline were reported for many variables with both second- and third-generation oral contraceptives without significant between-group differences. Also, in a combined analysis of nonsignificant changes, no consistent pattern of change emerged for any marker, with the exception of higher factor VII levels associated with third-generation oral contraceptives. However, factor VII is not related to venous thromboembolism risk. In addition, 1 cross-sectional study with an unvalidated assay reported a higher ratio of activated protein C sensitivity with third-generation oral contraceptives. Only 2 components of the hemostatic system (factor VII and activated protein C sensitivity ratio) emerged as potentially differentially affected by second- and third-generation oral contraceptives; the association with venous thromboembolism risk is questionable in the former case and unknown in the latter.

PIP: The initial finding of an increased risk of venous thromboembolism in users of third-generation oral contraceptives (OCs) has not been confirmed in recent, more methodologically refined studies. This article reviews 17 prospective studies with healthy volunteers and one cross-sectional study that compared second- and third-generation OCs in terms of their effects on markers of hemostasis. Significant changes from baseline were reported for many variables with both second- and third-generation OCs. For example, activated partial prothrombin clotting time, protein S, and tissue plasminogen activator and its inhibitor were reduced during OC treatment. However, none of the studies reported statistically significant differences between treatment groups for any of these markers. In a combined analysis of nonsignificant changes, no consistent pattern emerged for any coagulation or fibrinolysis parameter with the exception of higher factor VII levels (not related to venous thromboembolism risk) associated with third-generation formulations. The cross-sectional study with an unvalidated assay found a higher ratio of activated C protein sensitivity with third-generation OCs. Only two components of the hemostatic system--factor VII and activated protein C sensitivity ratio--emerged as potentially differentially affected by second- and third-generation OCs. The association with venous thromboembolism risk is questionable in the former cases and unknown in the latter.

Thrombotic diseases in young women and the influence of oral contraceptives.

OBJECTIVE: In the evaluation of the clinical impact of thrombotic diseases in young women, age-specific incidence rates must be calculated for both arterial and venous thrombotic diseases, but also the case-fatality rate and figures for the clinical consequences among those who survive thrombosis must be included. The aim of this analysis was to quantify the clinical impacts of both arterial and venous thrombotic diseases among young, nonpregnant women and thereafter to assess the influences of oral contraceptives on these measures. STUDY DESIGN: Nationwide register data on the morbidity and mortality of venous thromboembolism, myocardial infarction, and thrombotic stroke in Denmark, 1980-1993, and 3 ongoing case-control studies to assess the influence of oral contraceptives on the risk for development of these thrombotic diseases. RESULTS: In women 15-29 years old venous thromboembolism is about twice as common as arterial complications, whereas in women 30-44 years old the number of arterial complications exceeds that of venous diseases by about 50%. The mortality rate from arterial diseases is 3.5 times higher than that from venous diseases among women <30 years old and 8.5 times higher than that from venous diseases in women 30-44 years old. The proportion of women with a significant disability among women who had an arterial complication was about 30%; the proportion was about 5% among women with venous thromboembolism. CONCLUSION: Anticipating a differential influence on venous and arterial diseases from oral contraceptives with second- and third-generation progestogens, it was calculated that users of oral contraceptives with second-generation progestogens had 30% greater increased risk of thrombotic diseases, 260% greater increased risk of thrombotic deaths, and 220% greater increased risk of thrombotic disability than users of oral contraceptives with third-generation progestogens.

PIP: The influence of oral contraceptive (OC) use in young women on the risk of development of venous thromboembolism, myocardial infarction, and thrombotic stroke was assessed through an analysis of nationwide register data from Denmark for 1980-93 and for 1994-95 from three ongoing case-control studies. All three diseases increased rapidly with increasing age; the arterial diseases increased almost exponentially, while the venous diseases increased more linearly. Venous thromboembolism was almost twice as prevalent as arterial complications in women 15-29 years old, while the number of arterial complications exceeded that of venous diseases by about 50% in women 30-44 years of age. Mortality from arterial diseases was 3.5 times higher than that from venous diseases among women under 30 years of age and 8.5 times higher than that from venous diseases in women 30-44 years old. The proportion of women with a significant disability was about 30% among those with an arterial complication; this proportion was 5% among women with venous thromboembolism. Users of OCs with second-generation progestogens had a 30% greater increased risk of thrombotic diseases, a 260% greater increased risk of thrombotic mortality, and a 220% greater increased risk of thrombotic disability than users of OCs with third-generation progestogens.

Myocardial infarction and stroke in young women: what is the impact of oral contraceptives?

Recent discussions have centered on the small apparent risk increase for venous thromboembolism found with newer oral contraceptives (third-generation oral contraceptives containing the progestins desogestrel and gestodene) compared with older oral contraceptives (second-generation). This article reviews the studies addressing the association between oral contraceptive use and thromboembolic conditions affecting the arterial system, ischemic stroke, and myocardial infarction. Differences are found between a US database study, which showed no risk of ischemic stroke or myocardial infarction associated with low-dose oral contraceptive use, and the European studies, which showed oral contraceptive use in general to be associated with increased risks of ischemic stroke and myocardial infarction. The European studies showed no difference between oral contraceptive generations with respect to the occurrence of ischemic stroke; however, the risk of myocardial infarction associated with oral contraceptive use was consistently lower for third- than for second-generation oral contraceptives. Although there seems to be no differential risk of ischemic stroke associated with oral contraceptive generations, third-generation oral contraceptives appear to be consistently associated with no excess risk of myocardial infarction. In all instances, however, cardiovascular risk factors other than oral contraceptive use play the predominant role in the occurrence of ischemic stroke and myocardial infarction.

PIP: This article reviews seven recent studies that addressed the association between second- and third-generation oral contraceptive (OC) use and the risk of ischemic stroke and/or myocardial infarction. The one US study found no risk of ischemic stroke or myocardial infarction with low-dose OC use, while the European studies detected increased risks of both these events. The European studies showed no difference between OC generations in terms of the occurrence of ischemic stroke; however, the risk of myocardial infarction was consistently lower for third- compared with second-generation OCs. In all instances, cardiovascular risk factors other than OC use, especially smoking and hypertension, play the predominant role in the occurrence of both ischemic stroke and myocardial infarction.

Oral contraceptives and venous thromboembolic disease: the findings from database studies in the United Kingdom and Germany.

OBJECTIVE: Three research articles published in late 1995 and early 1996 suggested that oral contraceptives containing either of the newer progestogens (gestodene or desogestrel) could be associated with an increased risk of venous thromboembolism. During the months after the initial publications, the results have been scrutinized with great care and further studies have been published. The findings of 2 recent database studies, 1 in the United Kingdom and 1 in Germany, are presented in this article. PATTERNS OF USE: The average age of users of combined oral contraceptives in Germany was 27 years, compared with 26 years in the United Kingdom. In Germany the use of gestodene-based products was lower than that in the United Kingdom. In the United Kingdom the users of desogestrel with 20 microg ethinyl estradiol (Mercilon) were older than the users of desogestrel with 30 microg ethinyl estradiol (Marvelon). CRUDE INCIDENCE: The crude incidence of venous thromboembolism in the UK study was 4.1 cases/10,000 woman-y exposure to combined oral contraceptives. In Germany it was 4.2 cases/10,000 woman-y. In Germany the rates among users of second-generation combined oral contraceptives were higher than those among users of third-generation products. The reverse was the case in the United Kingdom. In the United Kingdom the crude incidence rates were higher for the 20 microg estrogen desogestrel product than for the 30 microg product. CASE-CONTROL ANALYSIS: The adjusted odds ratios in the UK study did not show significant increases for desogestrel or gestodene compared with levonorgestrel products. There were inconsistencies in the results among centers in the 2 international studies (the World Health Organization and Transnational studies). In both there was a consistent inverse dose-response relationship with estrogen in all centers. CONCLUSION: The limitations of the observational studies are such that the hypothesis that the newer progestogens are more likely to cause venous thromboembolism cannot be proved.

PIP: Research articles published in 1995-96 suggested that oral contraceptives (OCs) containing desogestrel or gestodene are associated with an increased risk of venous thromboembolism. This paper presents the findings of two more recent studies on this association, one from the UK and the other from Germany, both of which were based on general practice computer-generated clinical databases. The median age of OC users was 26 years in the UK study and 27 years in the German study. The crude incidence of venous thromboembolism per 10,000 woman-years of OC exposure was 4.1 cases in the UK study and 4.2 cases in Germany. In Germany, this rate was higher among users of second-generation OCs (4.03 cases per 10,000 woman-years) than third-generation OCs (3.95 cases per 10,000 woman-years). In the UK, the reverse pattern was found: 4.96 and 3.10 cases per 10,000 woman-years for third- and second-generation products, respectively. Moreover, crude incidence rates were higher for the 20 mcg estrogen-desogestrel formulation than for the OC containing desogestrel and 30 mcg of estrogen--a biologically implausible finding. The adjusted odds ratios in the UK study did not show any significant increases in venous thromboembolism risk for desogestrel or gestodene compared with levonorgestrel. Overall, these findings fail to provide support for the hypothesis that the newer progestogens are more likely to cause venous thromboembolism.

Effect of ritonavir on the pharmacokinetics of ethinyl oestradiol in healthy female volunteers.

AIMS: To assess the effects of the protease inhibitor ritonavir on the pharmacokinetics of ethinyl oestradiol in healthy female volunteers. METHODS: This was an open-label, single centre study in 23 subjects who received two single doses of oral contraceptive containing 50 microg ethinyl oestradiol on Day 1 (alone) and on Day 29 during concomitant ritonavir. Each subject received 16 days of every 12 h doses of ritonavir from Day 15 through Day 30. Blood samples were collected for serum ethinyl oestradiol concentrations for 48 h after each dose and for plasma ritonavir on Day 29 at 0 and 4 h postdose. RESULTS: Statistically significant decreases in ethinyl oestradiol mean Cmax (-32%) and mean AUC (-41%), and a statistically significant increase in the mean terminal elimination rate constant (+31%) were observed during concomitant ritonavir. The harmonic mean terminal half-life decreased from 17 h to 13 h during concomitant ritonavir. No statistically significant change was noted in tmax. The ratios of means (95% confidence intervals) for Cmax and AUC were 0.682 (0.612-0.758) and 0.595 (0.506-0.694), respectively. The changes in ethinyl oestradiol pharmacokinetics were consistent with an increase in clearance from enzymatic induction of glucuronidation and/or cytochrome P450 hydroxylation. Mean steady-state ritonavir concentrations of 6.5 and 13.4 microg ml(-1) were observed at 0 and 4 h postdose, respectively. CONCLUSIONS: Considering the extent of the decrease in ethinyl oestradiol concentrations, the use of alternate contraceptive measures should be considered when ritonavir is being administered.

PIP: The protease inhibitor ritonavir has demonstrated broad-spectrum ability against HIV 1 and 2. The present study investigated the drug interaction potential of steady-state ritonavir on single dose ethinyl estradiol pharmacokinetics. 23 healthy women (mean age, 34 years) received an oral contraceptive (OC) containing 50 mcg of ethinyl estradiol and 1 mg of ethynodiol on days 1 and 29, while 500 mg of ritonavir was administered every 12 hours on days 15-30. After administration of a single dose of OC, serum ethinyl estradiol concentrations peaked at 4 hours and declined thereafter, with a typical half-life of 17 hours. Administration of the second OC on day 29, after 16 days of continuous ritonavir, resulted in a 32% lower ethinyl estradiol mean maximum concentration (p 0.001) and a 41% lower mean area under curve (p 0.001) compared with OC administration alone. In addition, the mean terminal elimination rate constant increased by 31% (p 0.001) with concomitant ritonavir. The changes in ethinyl estradiol pharmacokinetics were consistent with an increase in clearance from enzymatic induction of glucuronidation and/or cytochrome P450 hydroxylation. Mean steady-state ritonavir concentrations of 6.5 and 13.4 mcg/ml were observed at 0 and 4 hours post-dose, respectively. The interaction observed in this study is likely to be clinically significant, with an increased risk of OC failure. Thus, use of alternate contraceptive measures should be recommended when ritonavir is being administered.

Bone density in long term users of depot medroxyprogesterone acetate.

OBJECTIVE: To identify any adverse effect on bone density in long term users of depot medroxyprogesterone acetate (DMPA) for contraception. DESIGN: Cross-sectional measurement of bone density in users with amenorrhoea of more than one year or any woman using DMPA for more than five years. SETTING: Community Family Planning Clinics in Portsmouth and Manchester. POPULATION: One hundred and eighty-five women aged 17-52 years (mean 33.3 years) who had used DMPA for between 1 and 16 years and were attending the clinics for further injections, between August 1994 and August 1996. METHODS: Dual energy X-ray measurement of bone density of femoral neck and lumbar spine, and venous blood sample taken just prior to the next injection of DMPA. MAIN OUTCOME MEASURES: Bone density of femoral neck and lumbar spine and serum oestradiol in relationship to years of DMPA use and duration of amenorrhoea. RESULTS: Most women (n=153) had serum oestradiol levels < 150 pmol/l. Despite this, the mean bone density of the lumbar spine compared with the population mean for women aged 20-59 years gave a Z score (95% CI) of -0.332 (-0.510 to -0.154). There was no significant difference in the mean density of the femoral neck from the normal population mean. CONCLUSION: Despite amenorrhoea and low serum oestradiol, this sample of long term DMPA users had bone density only minimally below the normal population mean. We therefore found no clinically important adverse effect on bone density and therefore no reason to recommend bone conserving measures, such as add-back oestrogen.

PIP: The effects on bone density of long-term depot medroxyprogesterone acetate (DMPA) use were investigated in a cross-sectional study of 185 clients 17-52 years of age at family planning clinics in Portsmouth and Manchester, England, who had been receiving contraceptive injections for 1-16 years (median, 5 years). Dual energy x-ray measurements of bone density of the femoral neck and lumbar spine, as well as venous blood samples, were taken prior to the women's next DMPA injection (1994-96). 153 women had serum estradiol levels under 150 pmol/l--the value considered adequate to maintain bone density. The mean bone density of the lumbar spine compared with the population mean for women 20-59 years old yielded a Z score of minus 0.332 (95% confidence interval, -0.510 to -0.154; p 0.001). There was a weak, nonsignificant correlation between lumbar spine Z score and years of DMPA use. Mean density of the femoral neck did not differ significantly from the normal population mean. There was no significant correlation between serum estradiol level and either bone density score. Overall, these findings provide no evidence that DMPA-induced amenorrhea places women at significant risk of further bone loss or that supplemental estrogen is required.

Resistance to activated protein C, highly prevalent amongst users of oral contraceptives with venous thromboembolism.

OBJECTIVE: Inherited resistance to activated protein C (APC resistance), which is caused by a single point mutation in the factor V gene, is a frequent risk factor for venous thromboembolism. The aim of this study was to determine the prevalence of APC resistance and other coagulation disorders in fertile women with venous thromboembolism and also the risk factors these women had been exposed to in connection with thromboembolic events. DESIGN: A retrospective, case-control study of 36 month duration. SETTING: The study was carried out at Blekinge Hospital, Karlskrona, Sweden. SUBJECTS: The study population comprised 27 fertile women age 16-47 years with thromboembolic complications, referred to the department of Internal Medicine at Blekinge Hospital in Karlskrona during a 36-month period. RESULTS: APC resistance was found in 10 out of 27 women. APC resistance was associated with treatment with oral contraceptives in five out of six women and with pregnancy in one of seven women. All women with resistance to APC developed venous thrombosis in association with a predisposing situation (risk situation) such as surgery, trauma, immobilization, pregnancy, inflammatory state or the use of oral contraceptives. Amongst women not resistant to APC, all but one developed thrombosis in connection with a risk situation. CONCLUSION: APC resistance was found to be highly prevalent amongst fertile women with a history of thromboembolic complication occurring during their use of oral contraceptives.

PIP: Resistance to activated protein C (APC), caused by a single point mutation in the factor V gene, is a significant risk factor for venous thromboembolism. Studies conducted in Sweden have found prevalences of APC resistance ranging from 7% to 15%. The prevalence of this and other risk factors was investigated retrospectively in 27 fertile women 16-47 years of age admitted to Blekinge Hospital (Karlskrona, Sweden) with venous thromboembolism during a 36-month period (1992-94). APC resistance was detected in 10 (37%) of these women, 7 of whom had a family history of venous thrombosis. All 10 women with APC resistance had been exposed to at least one other risk factor. Oral contraceptive (OC) use was reported by 5 women in the APC resistance group and by 1 non-APC resistant case; 5 of these OC users took a pill containing desogestrel. 7 women with venous thromboembolism (1 in the APC-resistant group) were pregnant or postpartum. Other risk factors included surgery (n = 5) and pregnancy-related immobilization (n = 4).