Erik Weiner

Plasma levels of d-norgestrel after oral administration.

Abstract Peripheral plasma levels of d-norgestrel were determined by radioimmunoassay in five women after oral administration of 30, 250 and 1000 μg d-norgestrel. Peak levels of d-norgestrel in plasma were mostly seen within 2 hours after intake of the pills. The peak concentrations found were 0.9–2.0 ng/ml, 3.3–5.1 ng/ml and 14.0–23 ng/ml, respectively, for the three doses administered. The plasma concentrations of d-norgestrel 24 hours after ingestion of the pills were 0.05–0.14 ng/ml, 0.3–0.7 ng/ml and 1.8–5.2 ng/ml, respectively. The plasma half-life of d-norgestrel for the period 8–24 hours following the tablet intake was around 13 hours but varied considerably among the participants. For the period 24–72 hours the corresponding half-life was around 21 hours. During 3 weeks treatment with combined oral contraceptives containing d-norgestrel and ethinyl estradiol, increasing d-norgestrel levels in plasma were found in most of the subjects. Patients on low dose gestagen pills (30 μg d-norgestrel) showed constant plasma levels of d-norgestrel throughout a treatment period of 3 weeks. The results obtained in this study suggest that the gradual increase of the d-norgestrel levels found in plasma when d-norgestrel is given in combination with ethinyl estradiol might be due to increased levels of sex hormone binding globulin, the carrier protein for d-norgestrel, rather than to accumulation caused by a long biological half-life.

Plasma levels of norethindrone after i.m. injection of 200 mg norethindrone enanthate.

Abstract The plasma levels of norethindrone were measured with a radioimmunoassay after an intramuscular injection of 200 mg of norethindrone enanthate in five healthy women. After an initial peak of norethindrone between 8–14.5 ng/ml, a gradual decline followed. The concentration of 1 ng/ml was reached after approximately 45 days. The plasma pattern of norethindrone was very similar in all the five volunteers. Ovulation was suppressed during the period with high levels of norethindrone. During the second half of the 12 weeks of treatment, ovulation occurred and the norethindrone is likely to achieve its contraceptive effect in the same way as in the minipill formulation.

Contraception with d-norgestrei silastic rods. Plasma levels of d-norgestrel and influence on the ovarian function

Abstract Three silastic rods impregnated with d-norgestrel each containing 40 mg of the gestagen, were inserted subcutaneously in the left forearm of four women and left in place for 100–458 days. After about 300 days of treatment a daily oral dose of 50 Mg ethinylestradiol was given to three of the participants during 21 days, in order to increase the concentration of sex hormone binding globulin in plasma. The plasma levels of progesterone, estradiol and d-norgestrel were analysed by radioimmunoassay. The study demonstrated fairly constant plasma levels of d-norgestrel during treatment. The concentrations observed were in the range found 4–6 hours after intake of the mini-pill formulation of d-norgestrel (0.03 mg). When the sex hormone binding globulin levels were increased by oral ethinylestradiol treatment in the subjects with previous constant d-norgestrel levels in plasma, the d-norgestrel levels increased two- to sixfold indicating that sex hornome binding globulin is the main carrier protein for d-norgestrel. The concentrations of d-norgestrel in plasma did not inhibit the baseline levels of estradiol in plasma, but ovulation was inhibited during the first year of treatment. Ovulatory pattern of progesterone was restored within 20 days after removal of the rods. The amount of d-norgestrel lost from the rods during treatment suggest a contraceptive efficacy of at least 2 years.

Effects on sex hormone binding globulin of different oral contraceptives containing norethisterone and lynestrenol.

Six combined oral contraceptive drugs containing ethinyloestradiol or mestranol and norethisterone or lynestrenol were studied throughout six 21‐day cycles in healthy female volunteers. There was always one menstrual cycle without treatment between every treatment cycle. Plasma levels of norethisterone were determined throughout treatment by use of a specific radioimmunoassay. Sex hormone binding globulin (SHBG) was measured by an ammonium sulphate precipitation method at the beginning and at the end of each treatment cycle. The results indicated an accumulation of norethisterone in plasma when 1 to 3 mg of norethisterone or lynestrenol was given. There was no obvious accumulation during treatment with 0·5 mg norethisterone. SHBG increased during treatment with all combinations studied. However, this increase was most pronounced with the 50 úg ethinyloestradiol/1 mg lynestrenol, 50 μg mestranol/1 mg norethisterone and 35 μg ethinyloestradiol/0·5 mg norethisterone combinations. There was no statistically significant increase in SHBG with 50 μg ethinyloestradiol/2·5 mg lynestrenol or 50 μg ethinyloestradiol/3 mg norethisterone acetate combinations. The results indicated that the induction of SHBG by the synthetic oestrogens was antagonized by the progestogens in a dose‐dependent manner. The effect on SHBG by a combined preparation could be one assessment of the oestrogenicity or androgenicity of the preparation.

Endometrial effects of levonorgestrel and estradiol: A scanning electron microscopic study of the luminal epithelium

Fertile women in the follicular phase possessed an uterine luminal surface with many ciliated cells and with non-ciliated cells, which carried numerous, fairly long microvilli. A moderate number of the non-ciliated cells had an irregular surface with small apical protrusions. Postmenopausal women had an endometrial surface containing rather flat cells. Ciliated cells were seldon encountered, and the non-ciliated cells possessed mostly only few short microvilli. When menopausal women had been wearing estradiol-containing intravaginal rings for three weeks, the uterine surface had developed many ciliated cells, and the non-ciliated cells now possessed many long microvilli. This appearance resembles that appearing during the follicular phase. Fertile women with levonorgestrel-containing subdermal implants or intravaginal rings showed a surface epithelium with few ciliated cells and with non-ciliated cells possessing short and irregular microvilli; that is, an epithelium less developed than that from a cyclic women. Adding estradiol to the levonorgestrel-containing intravaginal rings resulted in an estrogen response with an increase in number and length of the microvilli and an appearance of a few small apical protrusions.

Subdermal norethindrone pellets — A method for contraception?

The mode of action of compressed pellets containing 85 per cent norethindrone (NET) and 15 per cent cholesterol was studied. Four pellets were inserted subcutaneously, in each of five healthy volunteers and left in place for 200--229 days. The NET content of the pellets varied between 23.9 mg and 25.6 mg; and the cholesterol content between 4.2 mg and 4.5 mg. Plasma levels of NET, estradiol and progesterone were determined by radioimmunoassays. Plasma levels of NET varied mostly between 1--2 ng/ml the first month after insertion. After two months plasma levels of NET ranged between 0.5 ng/ml and 1 ng/ml in all volunteers and there was a gradual decrease of the plasma NET levels throughout treatment. Pronounced day-to-day variations in plasma NET levels were recorded. The release rates of NET was calculated to be between 187 micrograms/day and 243 micrograms/day among the five volunteers. Ovulations occurred in four out of five subjects during treatment. This study indicates that the release of gestagen from four NET pellets was only initially high enough to completely inhibit ovulation and that to accomplish full contraceptive efficacy, a higher dose, i.e. more pellets, would have to be inserted.

NEW DELIVERY SYSTEMS FOR D‐NORGESTREL

Various new delivery systems for d-norgestrel the most potent avail able contraceptive gestagen are discussed. Numerous studies of d-norgestrel administered via subdermal capsules and rods intravaginal rings and IUDs have been conducted. Bleeding irregularities are the primary clinical problem associated with d-norgestrel. The release rates and plasma levels of the gestagen for the various systems studied are reported. Advantages and disadvantages of the delivery systems are discussed.

OVARIAN FUNCTION DURING TREATMENT WITH GESTAGEN IMPREGNATED VAGINAL RINGS

Soft rings made of a silicone polymer impiegnated with norgestrel were inserted into the vagina of eight healthy women at the end of the menstrual bleeding. Ovarian function was followed by repeated estimations of the plasma levels of oestradiol and progesterone using a radioimmunoassay method. Plasma levels of dnorgestrel were also determined by radioimmunoassay. None of the women ovulated during treatment as judged from their progesterone and oestradiol levels. In the five women treated with rings with a rapid release initially high levels of d-norgestrel were followed by rapidly decreasing levels. Four out of five women had withdrawal bleedings when the ring was removed. The fifth woman ovulated immediately after the ring was removed. No withdrawal bleeding occurred. In the three women treated with rings with a slow release of norgestrel more even plasma levels of d-norgestrel were found during treatment, but only one woman had a withdrawal bleeding when the ring was removed. No breakthrough bleedings or subjective side effects were registered. The rings were well tolerated by the women and their male partners.

Incorrect Diagnosis of Placental Insufficiency in a Patient with Pre‐Eclampsia

A case of pre‐eclampsia is described where suspicion of placental insufficiency arose due to low estriol levels and a positive oxytocin challenge test (OCT). The cause, however, of these findings was later proven to be strictly fetal. It is concluded that low estriol levels and a positive OCT may be caused by a decreased placental capacity but specific tests of placental function, as for instance estimations of HPL in plasma and/or a DHAS‐test, should be used to verify or rule out a suspicion of placental insufficiency.