Tapani Luukkainen

Endometrial morphology during long-term use of levonorgestrel-releasing intrauterine devices.

Summary Levonorgestrel-releasing intrauterine devices (IUD) were inserted in 92 women. Endometrial biopsies were taken between 3 months and 7 years after these insertions. Intrauterine release of Levonorgestrel resulted in endo-metrial glandular atrophy and decidualized stroma. Inflammation and necrosis were also seen as local signs of IUD use. The biopies were similar regardless of the duration of IUD use. Endometrial morphology returned to normal in biopsy specimens taken 1–3 months after IUD removal.

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.

TISSUE CONCENTRATIONS OF LEVONORGESTREL IN WOMEN USING A LEVONORGESTREL‐RELEASING IUD

Thirteen women who were scheduled for hysterectomy volunteered for the study. Nine women had a levonorgestrel‐releasing intrauterine contraceptive device inserted between 36 and 49 days prior to surgery and four women were on oral levonorgestrel treatment for 7 days prior to surgery. After the surgical removal of the uterus, samples of endometrial, myometrial, fallopian tube and fat tissue were obtained. Methods for measuring tissue concentrations of levonorgestrel were developed and the uptake of levonorgestrel by fat tissue in vitro was studied. The concentrations of levonorgestrel in myometrial, fallopian tube and fat tissue were all of the same order, of between 1 and 5 ng/g of wet weight of tissue, in both the intrauterine device group and the orally treated group. In the endometrium the levonorgestrel concentrations were many‐fold higher in the intrauterine device group. The in vitro experiments showed a rapid uptake of levonorgestrel and an unsaturability of the fat tissue by the steroid at the concentrations used. The fat tissue concentrations of levonorgestrel correlated with the plasma concentrations.

Binding of progestins to the glucocorticoid receptor: Correlation to their glucocorticoid-like effects on in vitro functions of human mononuclear leukocytes

A number of physiological and synthetic progestins were tested for their ability to compete with [3H]dexamethasone for the binding to the glucocorticoid receptor of human mononuclear leukocytes and their ability to elicit glucocorticoid-like effects on the same cells. As compared to the reference compound dexamethasone (relative receptor binding affinity defined as 100%), two potent synthetic progestins with a pregnane-type structure, megestrol acetate and medroxyprogesterone acetate, were found to display a considerable binding affinity towards the receptor (46 and 42%, respectively). The relative binding affinity of the naturally occurring ligand, cortisol, to the receptor was clearly lower (25%). The effective binding of medroxyprogesterone acetate to the glucocorticoid receptor was confirmed by direct binding studies utilizing a tritiated derivative of this steroid. No evidence for the existence of a specific progesterone receptor in human mononuclear leukocytes was obtained as judged by the results of competition experiments where a progesterone receptor-specific ligand [3H]Org 2058 was used. Medroxyprogesterone acetate and megestrol acetate also induced glucocorticoid-like effects on the lymphocyte functions. These included inhibition of the proliferative responses to the T-cell mitogens concanavalin A and phytohaemagglutinin and an enhanced accumulation of immunoglobulin secreting cells in pokeweed mitogen-stimulated cultures. The progestin effect appears to be mediated through a radiosensitive (suppressor) subpopulation of T lymphocytes. In contrast, the synthetic progestins related structurally to 19-nortestosterone, norethisterone and d-norgestrel, were virtually devoid of binding affinity towards the glucocorticoid receptor nor did they measurably influence the in vitro lymphocyte functions. These studies demonstrate that certain progestins in common clinical use probably possess inherent glucocorticoid activity and suggest that side effects attributable to this character (e.g. suppression of the pituitary-adrenal axis) might be expected when these compounds are used in pharmacological doses.

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.

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.

Pharmacokinetics and metabolism of RU 486.

The effects of dose on the initial pharmacokinetics and metabolism of an antiprogesterone steroid RU 486 (mifepristone) were studied in healthy female volunteers after administration of RU 486 as a single dose of 50-800 mg. The concentrations of RU 486 and its monodemethylated, dimethylated and hydroxylated non-demethylated metabolites were measured specifically after Chromosorb-column chromatography by HPLC. Their relative binding affinities to the human uterine progesterone receptor were also determined. Micromolar concentrations of the parent compound in blood were reached within the first hour after oral administration. The pharmacokinetics of RU 486 followed two distinct patterns in a dose-dependent fashion. With a low dose of 50 mg the pharmacokinetics followed an open two-compartment model with a half-life of over 27 h. With the doses of 100-800 mg the initial redistribution phase of 6-10 h was followed by zero-order kinetics up to 24 h or more. Importantly, after ingestion of doses higher than 100 mg of RU 486 there were no significant differences in plasma concentrations of RU 486 within the first 48 h, with the exception of plasma RU 486 concentrations at 2 h. After single oral administration of 200 mg unchanged RU 486 was found 10 days later in two subjects. The elimination phase half-life with this dose, calculated between day 5 and 6, was 24 h. Micromolar concentrations of monodemethylated, didemethylated and non-demethylated hydroxylated metabolites were measured within 1 h after oral administration of RU 486. In contrast to plasma RU 486 concentrations, circulating plasma concentrations of metabolites increased in a dose-dependent fashion. With higher doses the metabolite concentrations were close to, or even in excess to the parent compound. The relative binding affinities of RU 486, monodemethylated, didemethylated and hydroxylated metabolites (progesterone = 100%) to the human progesterone receptor were 232, 50, 21, and 36, respectively. The existence of a high affinity-limited capacity serum binding protein would explain the long half-life and the observed diverging dose-dependent pharmacokinetics. The extravasation of RU 486 after the saturation of serum binding sites would explain the blunted serum peak concentrations of RU 486 with higher doses. The return of the drug back to circulation thereafter explains the zero-order kinetics. High concentrations of circulating metabolites capable of binding to the progesterone receptor suggest a significant contribution of these steroids in the overall antiprogestational action.

Endometrial Morphology of Women Using A d-Norgestrel-Releasing Intrauterine Device *

Endometrial biopsies were obtained from 12 volunteers treated with d-norgestrel-releasing intrauterine devices (IUDs) with two different release rate. Four subjects scheduled for hysterectomy had d-norgestrel-releasing IUDs inserted approximately 1 month prior to surgery. The effect of d-norgestrel on the endometrium and fallopian tubes of the removed uteri was examined. A uniform suppression of the endometrium with glandular atrophy and decidualization of the stroma was found in all of the endometrial specimens. Moreover, changes similar to those observed during the luteal phase and early pregnancy could be seen in the tubal epithelium.

Ovarian function in amenorrheic and menstruating users of a levonorgestrel-releasing intrauterine device *

The ovarian function of 20 healthy users of a levonorgestrel-releasing intrauterine device was studied by measurements of plasma estradiol, progesterone, and levonorgestrel concentrations. Eight subjects were amenorrheic, and 12 had regular menstrual bleeding. Seventy-five percent of the subjects in both groups had ovulatory cycles. There was no difference between the mean levonorgestrel concentrations in the amenorrheic and regularly menstruating subjects. Estradiol function was undisturbed in the amenorrheic subjects with ovulatory cycles. The effect of levonorgestrel as a cause of amenorrhea is thought to be mainly of local nature. The intrauterine administration of levonorgestrel had only an occasional and weak effect on ovarian function.