Juhani Toivonen

Protective effect of intrauterine release of levonorgestrel on pelvic infection: three years comparative experience of levonorgestrel- and copper-releasing intrauterine devices.

A randomized, multicenter comparison of two intrauterine contraceptive devices (IUDs) was carried out. Nine hundred thirty-seven women were fitted with a copper-releasing IUD, the Nova-T, and 1821 women with an IUD that releases 20 jug of levonorgestrel daily. After 36 months, the cumulative gross rates of amenorrhea and hormonal side effects were significantly higher in the levonorgestrel-IUD users. The cumulative 36-month gross pregnancy rate was 3.7 for the Nova-T and 0.3 for the levonorgestrel IUD (P<.001), demonstrating the levonorgestrel IUDs high contraceptive efficacy. For the first time, a protective effect of the levonorgestrel IUD against pelvic inflammatory disease as compared with the Nova-T was seen statistically. The cumulative 36-month gross rate of pelvic inflammatory disease was 2.0 in Nova-T- and 0.5 in levonorgestrel-IUD users (P<.013). This significantly lowered incidence of pelvic inflammatory disease may help to solve one of the major concerns associated with intrauterine contraception.

Levonorgestrel-Releasing Intrauterine Device

The levonorgestrel-releasing (LNG) IUD is a simple Nova T device with a Silastic reservoir of levonorgestrel in the vertical arm. It releases 20 mcg/day over 5 years. LNG IUD is very effective (about 99%) at preventing unplanned pregnancies. Circulating levels of levonorgestrel peak within 24 hours after LNG IUD insertion and are much lower than the levels in the endometrium. The high endometrial concentrations of levonorgestrel bring about a considerable reduction in the amount of bleeding, particularly oligomenorrhea. Other beneficial effects include prevention of iron deficiency anemia and protection against pelvic inflammatory disease (PID). Special counseling about changes in menstruation patterns for both providers and users is needed to prevent unwarranted discontinuation of LNG IUD. Hormonal side effects should also be discussed. Discontinuation for amenorrhea is more likely in LNG IUD users than copper IUD users (4.5% vs. 0; p = .001). LNG IUD hormonal side effects are more likely to result in discontinuation than those of the copper-releasing IUD (9% vs. 1.7%; p = .001). On the other hand, LNG IUD users are less likely to stop use for pregnancy, bleeding, and PID than copper IUD users (0.3% vs. 4.1%, p = .001; 11.3% vs. 17.9%, p = .002; and 0.5% vs. 1.5%, p = .022, respectively). Levonorgestrel generally has an effect on the ovaries just during the 1st year of use. It causes scanty and thick cervical mucus, its major contraceptive mode of action. LNG IUD can treat idiopathic excessive menstrual bleeding.

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.

Levonorgestrel-releasing IUD as a method of contraception with therapeutic properties

The levonorgestrel-releasing intrauterine device LNg IUD is a new contraceptive method that combines the advantages of both hormonal and intrauterine contraception. It gives users non-contraceptive health benefits and can also be used as an effective therapy for menorrhagia. The local release of LNg within the endometrial cavity results in strong suppression of endometrial growth as the endometrium becomes insensitive to ovarian estradiol. The endometrial suppression is the reason for a significant reduction of menstrual blood loss or amenorrhea, and for the disappearance of dysmenorrhea. The bleeding pattern during the use of the LNg IUD is characterized by reduction of the blood loss and in the number of bleeding days per cycle. During the first two to three months of use, however, irregular spotting is common. The removal of the device results in a quick return of menstrual bleeding and fertility. The failure rate of copper-releasing IUDs, as with other methods of fertility regulation, is higher in young women and decreases with age. The LNg IUD, on the other hand, has the same low pregnancy rate in every age group of the users. The LNg IUD also gives protection against ectopic pregnancy and pelvic inflammatory disease and, by reducing menstrual blood loss, increases the body iron stores. The LNg IUD can be used to effectively treat menorrhagia. This has been demonstrated in studies with quantitative determination of menstrual blood loss. During the first year of use, the LNg IUD reduced menstrual blood loss by 90% from pretreatment levels. Comparative clinical trials with the LNg IUD cover more than 10,000 women-years of follow-up during use over five to seven years. The Pearl pregnancy rate in studies has been 0.0-0.2 per 100 women-years. The overall ectopic Pearl pregnancy rate is 0.02 per 100 woman-years. The LNg IUD is marketed in Denmark, Finland, Norway, Sweden and in the United Kingdom.

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.

The long-term effects of oral and transdermal postmenopausal hormone replacement therapy on nitric oxide, endothelin-1, prostacyclin, and thromboxane.

OBJECTIVE Oral postmenopausal hormone replacement therapy (HRT) decreases the risk of cardiovascular disorders, but the mechanisms of this protection are largely unknown. We compared the long-term effects of sequential oral HRT and transdermal HRT on vasodilatory nitric oxide and prostacyclin as well as vasoconstrictive endothelin- and thromboxane A2, all of which may be factors in the protective effect of HRT against cardiovascular disorders. DESIGN Prospective, randomized study. SETTING Department of Obstetrics and Gynecology at a university hospital. PATIENT(S) Fifty-two healthy postmenopausal female nonsmokers (n = 42) or smokers (n = 10) who had climacteric symptoms. INTERVENTION(S) The women received either oral HRT (2 mg of estradiol on days 1-12, 2 mg of estradiol plus 1 mg of norethisterone acetate on days 13-22, and 1 mg of estradiol on days 23-28; n = 21) or transdermal HRT (50 microg/d of estradiol on days 1-28 followed by 250 microg/d of norethisterone acetate on days 14-28; n = 21) for 1 year. Ten female smokers received transdermal HRT for 1 year. MAIN OUTCOME MEASURE(S) Plasma levels of nitrate as an index of nitric oxide production, endothelin-1, and urinary output of the prostacyclin metabolite (2,3-dinor-6-keto-PGF1alpha) and that of the thromboxane A2 metabolite (2,3-dinorthromboxane B2) were measured before and during the combined phases of the 2nd, 6th, and 12th treatment months. RESULT(S) Both regimens increased plasma estradiol levels and alleviated vasomotor symptoms. Neither regimen caused significant changes in nitrate, endothelin-1, prostacyclin, or thromboxane A2 in nonsmoking women. Female smokers had significantly higher levels of endothelin-1, which were significantly reduced by transdermal HRT at 6 months of treatment. CONCLUSION(S) Nitric oxide, endothelin-1, prostacyclin, and thromboxane A2 are not of primary importance in the protective effect of sequential oral HRT against cardiovascular disorders in otherwise healthy nonsmoking postmenopausal women. In this regard, transdermal HRT appears comparable to oral HRT. Postmenopausal female smokers have high levels of endothelin-1 that are reduced by transdermal HRT.

Randomized comparison of levonorgestrel- and copper-releasing intrauterine systems immediately after abortion, with 5 years’ follow-up

Women who seek an abortion are motivated to use contraceptive methods afterwards. Because the return of fertility after abortion is immediate, there is a need for effective and safe contraception promptly after the termination of pregnancy. A randomized trial of Mirena and NovaT intrauterine contraceptive devices inserted at the time of elective termination of pregnancy, duration no more than 12 weeks, is reported here. Women were randomized 2:1 resulting in 305 subjects with Mirena and 133 with NovaT as a segment of a larger study of 3000 women. In the Mirena group, two pregnancies at year 4 resulted in a final gross rate of 0.8 at 5 years, which was significantly (p < 0.0004) lower than the corresponding rate of 9.5 with NovaT. Terminations because of expulsion, bleeding problems, pain, pelvic inflammatory disease and other medical reasons were less common in the Mirena group, but not significantly different. The cumulative expulsion gross rate for NovaT at 5 years was 15.4 and for Mirena it was 10.5. Termination rates because of amenorrhea were low in both groups. It is concluded that both devices were well tolerated. Mirena was more effective and the rate of adverse events was lower than with NovaT. Special attention should be paid to the insertion procedure when carried out at the time of abortion.

Randomized comparison of oral and transdermal hormone replacement on carotid and uterine artery resistance to blood flow

Objective To compare the long-term effects of oral and transdermal hormone replacement therapy (HRT) on carotid and uterine vascular impedance. Methods Sixty-three postmenopausal women were randomized to 1 years treatment with oral or transdermal sequential combined HRT. Carotid and uterine artery pulsatility indices (PIs) were assessed by color Doppler at baseline, and after 2, 6, and 12 months of treatment. Fiftyeight women completed the trial, 27 in the oral and 31 in the transdermal group. In a subgroup of 30 women, we also performed Doppler measurements in the estrogen-progestin combined phase. The study had 90% power to detect a difference between treatment groups of 0.05 in the carotid artery and of 0.25 in uterine artery PI at the 5% significance level. Results The carotid PI decreased significantly (P < .001) and similarly during both regimens. This drop was already clearly detectable during the second month, from 0.97 (0.95, 1.01) (mean and 95% confidence intervals [CI]) to 0.94 (0.91, 0.97) in the oral and from 0.98 (0.94, 1.00) to 0.92 (0.89, 0.95) in the transdermal group, but it continued up to 12 months (0.85 [0.82, 0.88], 13% of baseline values in the oral group and 0.84 [0.81, 0.87], 14% in the transdermal group). In the uterine arteries, the drop in PI was steeper and greater and reached its maximum at 6 months (39% and 40%, respectively). Drops in carotid and uterine PI correlated positively with baseline PI values, but were not affected by patient age, time from menopause, previous HRT and smoking. Addition of norethisterone acetate did not counteract drops in carotid and uterine PI in either group. Conclusion Oral and transdermal sequential HRT are similarly effective at 1 year in reducing impedance to flow in carotid and uterine circulation. This long-term vascular effect might explain how HRT protects women from cardio-vascular disease.

Return of Ovulation After Abortion and After Discontinuation of Oral Contraceptives

The return of ovulation after abortion and discontinuation of oral contraceptives was determined by plasma progesterone measurements. Plasma samples were obtained from 67 women at 3 to 6 weeks after abortion and in two groups of postabortion women at 3 to 6 weeks after cessation of oral contraceptives. In the first of these latter two groups, 50 women started taking the pills (containing 30 microgram of ethinylestradiol and 150 microgram of levonorgestrel) immediately after abortion, and the second group of 29 women started taking the pills from the first postabortion menses. Ovulation had recurred in 34% of the women 3 weeks after abortion and in 78% of the women at 6 weeks. The return of ovulation had occured in approximately 55% at 3 weeks after cessation of oral contraceptives in both groups. At 6 weeks after cessation, approximately 85% of women had ovulated in both groups. Luteal function in these two groups was found to be equal and was significantly better in both groups than during the first postabortion cycle (P < 0.005). It is concluded that the early return of ovulation after abortion makes it necessary to commence effective contraception immediately after abortion. The immediate administration of oral contraceptives after abortion does not affect the return of ovulation after discontinuation of oral contraceptives.

Contraception with subdermal ST-1435 capsules: side-effects, endocrine profiles and liver function related to different lengths of capsules.

One Silastic capsule of 15 mm, 20 mm or 30 mm length was inserted subcutaneously into the ventral aspect of the left forearm or upper arm of 28 healthy women during menstrual bleeding or not later than on the seventh day of the menstrual cycle. A new capsule of the same length was inserted after six months and both capsules were removed twelve months after the first insertion. Side-effects, including changes in body weight, blood pressure, menstrual bleeding and liver function test results, were registered. Blood samples were taken from selected subjects twice a week during the 1st, 2nd, 3rd, 6th, 7th and 12th month of use. Plasma concentrations of ST-1435 were measured by radioimmunoassay and the effects of treatment on pituitary and ovarian function were determined by assaying plasma concentrations of LH, FSH, estradiol and progesterone. There were no differences in hormonal side-effects between subjects who had a 30 mm capsule or subjects who had 20 mm or 15 mm capsules, but subjects who had 20 or 15 mm capsules had significantly longer bleeding or spotting periods in comparison with subjects who had a 30 mm capsule. There were no changes in blood pressure, body weight or liver function test results in comparison with pre-insertion values. The plasma level of ST-1435 was not significantly higher during the use of 30 mm capsules than during the use of 20 or 15 mm capsules. During the use of the shorter ST-1435 capsules, plasma estradiol elevation and slightly suppressed FSH were seen, while the use of longer capsules resulted in a slight suppression of LH. Progesterone concentrations during monitored cycles indicated anovulation. No pregnancies occurred during the study period of one year. The continuation rate at one year was 71% in the 30 mm capsule group and 57% in the 20 and 15 mm capsule groups taken together.