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Transdermal estrogen with a levonorgestrel-releasing intrauterine device for climacteric complaints: clinical and endometrial responses.

OBJECTIVE: Our purpose was to study the effects of intrauterine release of a daily dose of 20 micrograms levonorgestrel by an intrauterine device on climacteric symptoms, bleeding pattern, and endometrial histologic features in postmenopausal women receiving transdermal estrogen replacement therapy. STUDY DESIGN: Forty parous postmenopausal women were randomly allocated into two groups for 1 year: 20 women receiving a continuous transdermal daily dose of 50 micrograms of estradiol had a levonorgestrel-releasing intrauterine contraceptive device inserted, and the control group of 20 women received a continuous oral dose of 2 mg of estradiol valerate and 1 mg of norethisterone acetate daily. The climacteric symptoms, bleeding patterns, endometrial thickness, and endometrial changes in biopsy samples were analyzed. Serum levels of estradiol in both groups and levonorgestrel levels in the intrauterine device group were also determined. RESULTS: Both treatment regimens effectively relieved climacteric symptoms. Spotting was more common in the intrauterine contraceptive device group than in the oral therapy group for the first 3 months. After that, the proportion of women without any bleeding was similar in both groups. Two patients in each group dropped out because of bleeding. CONCLUSION: These preliminary findings suggest that the levonorgestrel-releasing intrauterine contraceptive device is a useful alternative mode of progestin administration for certain selected women receiving estrogen replacement therapy.

Administration, Cutaneous↗

Resistance to activated protein C as a basis for venous thromboembolism associated with pregnancy and oral contraceptives.

OBJECTIVE: Inherited resistance to activate protein C, which is caused by a single factor V gene mutation, is a frequent risk factor for thrombosis. The purpose of this study was to determine the prevalence of activated protein C resistance in women with thromboembolic complications that had occurred in connection with pregnancy or use of oral contraceptives. STUDY DESIGN: Activated protein C resistance was analyzed in women with previous thromboembolic complications in connection with pregnancy (n = 34) or oral contraceptives (n = 28), in healthy fertile women (n = 57), and in women during normal pregnancy (n = 18). Results of the activated protein C resistance test were expressed as activated protein C ratios, values < 2 indicating activated protein C resistance. RESULTS: Activated protein C resistance was found in almost 60% of women with thromboembolic complications during pregnancy and in around 30% of women with thromboembolic complications during treatment with oral contraceptives. In nonpregnant controls approximately 10% had activated protein C resistance. In normal pregnancy activated protein C ratios were similar to those of normal controls. CONCLUSIONS: Activated protein C resistance, which is caused by a genetic defect in the factor V gene, was found to be highly prevalent in women with a history of thromboembolic complications during pregnancy. The gene defect is common in the general population, and the results evoke the question whether it would be reasonable to perform general screening for activated protein C resistance early during pregnancy or before prescription of oral contraceptives.

Adolescent↗

Effects of low-dose oral contraceptives on female whole saliva.

The composition and flow rate of paraffin-stimulated whole saliva were analysed in 22 women, of whom 11 used oral contraceptives and 11 did not. Ten men served as the controls. The salivary samples were collected during one month (oral contraceptive users and men), or during one menstrual cycle (non-users). The saliva analyses included flow rate, pH, buffer effect, sialic acid, thiocyanate, peroxidase, lysozyme, amylase, immunoglobulins A, G and M, total protein, mutans streptococci, lactobacilli, yeasts and total numbers of aerobic bacteria. The salivary buffer effect of oral contraceptive users was significantly (p less than 0.005) higher than that of non-users. All the other constituents showed intra- and interindividual variation in all groups, but with no apparent hormone-dependency.

Adult↗

The use of a contraceptive vaginal ring governed by the pattern of individual uterine bleeding.

Contraceptive vaginal rings (CVR) releasing levonorgestrel and estradiol were used for contraceptive purposes in eight women. They were instructed to remove the CVR for five days only, in the case of bleeding. Three selected subjects were followed by plasma sampling during the first 60 days of treatment. Plasma concentrations of levonorgestrel, progesterone, estradiol and gonadotropins were determined. All subjects kept bleeding records and were controlled clinically in the course of treatment. The subjects were protected an average of 163 days by the CVR. Three subjects used the CVR 170--180 days without removing it and two subjects had to remove the CVR only once. Two subjects experienced quite regular bleedings, and metrorrhagic bleeding was present in one case. No pregnancies were observed during the follow-up period of 1304 days. Clinical examination revealed no pathological findings. The vaginal mucosa tolerated the treatment well. Out of those subjects who were followed by plasma sampling, pituitary suppression was more marked in the subject with continuous use of CVR.

Adult↗

Intrauterine contraception with Nova-T and copper-T-200 during three years.

A randomized comparative trial on the clinical performance of two copper-releasing IUDs (Nova-T and Copper-T-200) was performed simultaneously in Denmark, Finland and Sweden. After three years the cumulative pregnancy rate was 1.9 for Nova-T and 5.0 for Copper-T. This difference in efficacy was statistically significant (p less than 0.001). Copper-T had a lower expulsion rate (p less than 0.05) in the total series but not in postmenstrual insertions. Differences between the two devices in other termination rates were not statistically significant. Analysis according to age and parity demonstrated that the pregnancy rate of Nova-T was lower than that of Copper-T in every age and parity group. The pregnancy rate of Nova-T was not effected by age or parity whereas the pregnancy rate and the expulsion rate of Copper-T decreased with increasing age and parity. The removal rate because of infection decreased markedly after the first year of use for both devices. The cumulative rate of removals for infection during the three years of use was not significantly correlated to age and there was no correlation to parity. The continuation rates increased with age and parity. The continuation rates of nulli- and primiparous women were almost identical with both devices and lower than continuation rates of women with 2 or three or more children. Only 11% of the women were lost to follow-up during 36 months. Nova-T had superior effectiveness in preventing undesired pregnancies when compared with Copper-T. The performance of Nova-T is less affected by age and parity then the performance of Copper-T. The silver core in copper wire gives a prolongation of the life-span for Nova-T. For these reasons, Nova-T appears to meet the requirements for an ideal IUD.

Adult↗

Contraception and pregnancy among young women in an urban Swedish population.

The reproductive history and use of contraception in a representative sample of 19-year-old women from the city of Göteborg is reported. Oral contraceptives (OC) were taken by 47%, 4% had an intrauterine device and 12% used a barrier method while 37% practiced no form of contraception. The type of OC used and reasons for discontinuation are presented. The duration of OC use was one year or less for 46% of the women and exceeded 3 years in only 10%. Major causes of discontinued OC were the result of side effects attributed by the woman to OC, or a fear of OC. There were 93 pregnancies reported in the population sample, resulting in the birth of 34 infants. Pregnancy was terminated by legal abortion in 51% of the reported pregnancies. The ready availability of a return visit to discuss possible side effects and fears resulting from the chosen method of contraception may improve continuity, thus reducing the number of legal abortions.

Abortion, Legal↗

The zoapatle IV--toxicological and clinical studies.

The zoapatle aqueous crude extract has been used in Mexico for the last 5 centuries for the induction of labor, treatment of post-partum bleeding problems, and as a menses inducer. Today, it is sold in street markets, and its long documented history of use by humans could be taken as indirect evidence of a lack of toxicity. Rigorous pharmacological and clinical studies described here, fully confirm the empirical observations.

Animals↗

Comparison of contraceptive acceptability of levonorgestrel and ethinyl oestradiol administered in one three-phasic (Trionetta) and one monophasic (Neovletta) version.

In a Swedish multicenter study, a total number of 835 women completed a total of 6472 treatment cycles. Half of them were allotted at random to use the monophasic oral contraceptive Neovletta, also known as Microgynon 30 (30 micrograms ethinyl oestradiol + 150 micrograms levonorgestrel in each tablet). The second half was allotted to Trionetta, also known as Triquilar, Trigynon and Logynon (6 tablets with 30 micrograms ethinyl oestradiol + 50 micrograms levonorgestrel, 5 tablets with 40 micrograms ethinyl oestradiol + 75 micrograms levonorgestrel and 10 tablets with 30 micrograms ethinyl oestradiol + 125 micrograms levonorgestrel). The latter version was also present in a 28-day version containing in addition 7 "placebo" tablets to be used in the otherwise tablet-free interval. The contraceptive reliability was excellent although one pregnancy occurred in the three-phase version. It could be attributed to patient failure. In all aspects of bleeding control, the three-phasic pill proved to be superior to the reference monophasic preparation. The extreme low incidence of missed withdrawal bleeding and stability already during the first months of use are noteworthy features. For both preparations, continuation rate was at six months of use about 85% and at 12 months it was a similar figure. The most common reason for withdrawal was bleeding, about 5% each for both preparation. No serious side-effects were reported. The study clearly indicates that the three-phasic version is a major improvement in spite of a considerably decreased total dose of the gestagen.

Clinical Trials as Topic↗

Oral contraceptive steroids do not promote the development or growth of prolactinomas.

Seventy women with prolactinomas, age 19-38 years, were studied in order to evaluate a possible relationship between the use of steroidal oral contraceptives (o.c.) and the development of prolactin-producing adenomas. Sixty-seven patients were admitted for investigation because of menstrual bleeding disturbances and three patients because of galactorrhea. Forty-three patients (61%) had used o.c. Thirty-six out of forty-three women (83%) experienced their menstrual disturbances and/or galactorrhea when using o.c. or immediately after discontinuing the pill. Patients who had used o.c. had shorter duration of symptoms, lower S-prolactin levels and less pronounced enlargement of the sella turcica. These tendencies indicate that o.c. lead to an earlier manifestation of clinically latent prolactin-producing tumours. With or without previous o.c., the patients showed a low total fertility rate, indicating a notably long, clinically undiagnosed period of disease. The accumulated usage of o.c. by the women with prolactinomas was not higher than among the total female population of the same age in Sweden. Furthermore, patients on o.c. for several years did not show a more advanced form of the disease than women who had not taken the pill. Thus, the present study provides no support for the hypothesis that o.c. promote the growth of prolactin-producing pituitary adenomas.

Adenoma↗

Hormonal contraception in diabetic women: acceptability and influence on diabetes control and ovarian function of a nonalkylated estrogen/progestogen compound.

The clinical acceptability and the influence on diabetes control were investigated in 50 women with insulin-dependent diabetes mellitus (IDDM) during intake of a combined nonalkylated estrogen/progestogen compound (4 mg 17-beta estradiol, 2 mg estriol and 1 mg norethindrone) for one year. In 6 IDDM women, the influence of the hormonal treatment on diabetes control and on ovarian function was investigated by measuring the concentration of glycosylated hemoglobin (Hb-Alc), fasting plasma glucose, serum estradiol, serum estrone, serum progesterone and sex hormone binding globulin (SHBG) capacity. No pregnancy occurred during the study and the overall continuation rate of 60% compare well with the continuation rate normally found in non-diabetic women after administration of conventional type oral contraceptives. No difficulties with diabetes control was registered and no significant changes in insulin requirements, 24-h urinary glucose excretion nd Hb-Alc were found. Ovulation was inhibited during the hormonal intake as judged by serum progesterone measurements. Serum estrone increased (p less than 0.05), but this had no influence on SHBG capacity, indicating that the estrogen/androgen balance was unchanged during treatment.

Adult↗

Contraception by Norplant subdermal capsules is not reliable in epileptic patients on anticonvulsant treatment.

The contraceptive efficacy of progestin-only contraception was studied in epileptic patients using NORPLANT subdermal capsules. The effect of anticonvulsants on levonorgestrel plasma levels was determined. NORPLANT subdermal capsules were inserted into nine epileptic women, and ten control women using no medication. Venous blood samples were taken at 0, 1, 3, 6, 9 and 12 months after insertion and the concentration of levonorgestrel was determined by radioimmunoassay. At 3 to 12 months, the overall mean concentration of plasma levonorgestrel was significantly lower in the six epileptics taking phenytoin alone or in combination with other anticonvulsants (203 +/- 128 pg/ml, mean +/- SD) than in the controls (325 +/- 135 pg/ml, p less than 0.01). After one year, nine of the control patients continued the use of NORPLANT and no pregnancies occurred. Two of the nine epileptics became pregnant during contraception by NORPLANT. They both used phenytoin and their plasma concentrations of levonorgestrel were low near the time of conception. Levonorgestrel released from the capsules had no apparent harmful effects on epilepsy and none of the patients reported an increase in seizure frequency. The results show that contraception by the progestin levonorgestrel is not reliable in epileptic patients using anticonvulsants known to induce metabolizing enzymes of the liver.

Adult↗

Long-term follow-up of children breast-fed by mothers using oral contraceptives.

In a long-term follow-up study 48 breast-fed children, whose mothers had used oral contraceptives containing 50 micrograms of ethinylestradiol while lactating, were compared to a matched control group whose mothers had not used any hormonal contraceptives during lactation. In spite of a very large number of data collected from several different sources of information, no effect could be demonstrated of the ingested steroid, neither upon the panorama of diseases nor upon intellectual or psychological behaviour of the infants and children up to 8 years of age. The mothers who used oral contraceptives lactated a significantly shorter period of time than the controls, but no differences were found in weight gain and height increase in the children between cases and controls.

Breast Feeding↗

Androgen levels in women using Norplant implants.

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

Acne Vulgaris↗

Five years' experience with levonorgestrel-releasing IUDs.

Two levonorgestrel-releasing IUDs and a copper-releasing IUD of the same shape were studied in a randomized comparative study over five years. The levonorgestrel-releasing IUDs released 20 micrograms or 30 micrograms per day. The Pearl index during the 10,600 woman-months of LNG-IUD use was 0.11. The control device releasing copper had a Pearl index of 1.6. The amount and duration of menstrual bleeding was greatly reduced, leading to a high incidence of oligo- or amenorrhea. The continuation rate in this pioneer trial was 53 per 100 users for the levonorgestrel-releasing IUD (LNG-IUDs) and 50 per 100 users for the copper-releasing IUD (Nova T). The removal rates for reasons other than amenorrhea were not significantly different. Discontinuation because of amenorrhea occurred during the first two years, the cumulative termination rate for this reason was 11.6 per 100 users at five years. The LNG-IUDs removed for investigation after five years of use revealed that the devices contained about 40 percent of the original load. The effective lifespan of the device has been demonstrated by this study to be five years; the residual steroid gives an additional safety period of two more years. The LNG-IUD is a highly effective reversible contraceptive method, which strongly reduced the amount and duration of bleeding. During the first two months there is scanty but frequent spotting which, like the high incidence of oligo- and/or amenorrhea, requires counselling of health personnel and women using LNG-IUDs.

Adult↗

Bacterial flora of the cervix in women using an intrauterine device.

The cervical bacterial flora of 18 healthy, parous, sexually active women was analysed before, and 3-5 months after insertion of a copper-releasing intrauterine device (IUD) and after long-term use of an IUD for 3-5.5 years in another nine women. No significant differences were found in the number of aerobic bacteria isolated before or after IUD insertion or after long-term use of an IUD. In contrast to aerobic bacteria, significantly more anaerobes were isolated in the cervix of women having used an IUD for several years when compared to those using barrier contraception with a condom. None of the women had clinical signs of pelvic infection and a cervical bacterial flora rich in anaerobes can be regarded as a normal finding in healthy sexually active women using an IUD for contraception.

Adult↗

Effective contraception with the levonorgestrel-releasing intrauterine device: 12-month report of a European multicenter study.

The use-effectiveness of an intrauterine contraceptive device releasing 20 mcg of levonorgestrel daily (Lng-IUD), and of a Nova T copper-releasing IUD, were studied in a randomized, comparative multicenter trial. The Lng-IUD was inserted in 1821, and the Nova T in 937 women. The 12-month net pregnancy rate with the Lng-IUD (0.1 per hundred women) was significantly lower than that with the Nova T (0.9 per hundred). Removal rates for menstrual problems and/or pain were similar for the two methods (net rates 7.5 and 8.7, respectively). The 12-month continuation rates were 82.2 for the Nova T and 79.7 for the Lng-IUD. The reduction of the bleeding led to oligomenorrhea and amenorrhea in users of the Lng-IUD; the removal rate for these reasons was 1.4. The removal rate for hormonal side effects with the Lng-IUD was 2.4. Blood hemoglobin concentrations increased among users of the Lng-IUD and decreased among users of the Nova T. The results show that the Lng-IUD was a highly effective contraceptive method which reduced menstrual bleeding. It is a promising alternative for women desiring a highly effective method for long-term use.

Adult↗