Arne Victor

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.

Peripheral plasma levels of d-norgestrel in women after oral administration of d-norgestrel and when using intravaginal rings impregnated with dl-norgestrel

Abstract Peripheral plasma levels of progesterone, estradiol and d-norgestrel were determined by radioimmunoassay in five women using silastic intravaginal rings (IVR), homogenously impregnated with 50 mg of dl-norgestrel and in three women after oral intake of 250 and 30 μg of d-norgestrel. The radioimmunoassay for d-norgestrel utilized the crossreaction with a norethindrone antiserum. lodinated histamine was conjugated to d-norgestrel-3-(0-carboxymethyl)-oxime and the conjugate used as a tracer. It is concluded that this is a useful method for preparing a specific tracer for d-norgestrel. The plasma levels of progesterone and estradiol were depressed to early follicular phase levels during treatment with the IVRs. After an initial peak of 2.9–8.5 ng/ml on day 2–4, d-norgestrel levels decreased to 0.7–4.0 ng/ml at the end of treatment. Oral administration of 250 and 30 μg of d-norgestrel gave rise to peak plasma levels of 4–7 ng/ml and 1.1–2.8 ng/ml, respectively. The initial plasma half-life of d-norgestrel was found to be approximately three hours and the second half-life about 18 hours. A comparison between the plasma levels of d-norgestrel reached in women using IVRs and the levels reached after oral ingestion of d-norgestrel indicate that the rings used, during the main period of treatment, deliver more dnorgestrel than is needed for contraceptive purposes.

Comparison of the metabolic effects of two hormonal contraceptive methods: An oral formulation and a vaginal ring II. Serum lipoproteins and apolipoproteins

In a long-term, prospective study the effects on lipoprotein lipids and apolipoproteins (apo) of a combined oral contraceptive (OC) (30 micro gram ethinylestradiol and 150 micro gram levonorgestrel) and a contraceptive vaginal ring (CVR) releasing estradiol (about 180 micro gram per day) and levonorgestrel (about 290 micro gram per day) were compared. The two treatments induced significantly different effects. In the OC group the lipoprotein-lipid concentrations showed only minor changes, but apolipoproteins (apo) B and A-I increased by about 15%. In contrast, during treatment with the CVR there was a 25% decrement of cholesterol in high density lipoprotein (HDL) and at most 10% in low density lipoprotein (LDL) cholesterol, with only minor effects on apo B and A-I. The ratio of LDL and HDL cholesterol increased in the CVR group but not in the OC group. The results also indicate a change in the composition of the LDL and HDL particles, with an altered lipid/protein ratio, during both contraceptive treatments. Despite the impressive relative increase in LDL:HDL ratio in the contraceptive ring group, the average absolute value of this ratio did not reach the mena for healthy men.

Pharmacokinetic observations on medroxyprogesterone acetate administered orally and intravaginally

Abstract Plasma levels of medroxyprogesterone acetate (MPA) were determined by radioimmunoassay in five women after oral administration of 10 mg of MPA and during treatment with intravaginal rings homogenously impregnated with 100 mg of MPA. Peak plasma levels of MPA of 1.15–5.15 ng/ml were reached within two hours after oral administration. The levels thereafter rapidly declined being 0.09–0.35 ng/ml at twelve hours. During IVR treatment rather stable plasma levels between 0.37 and 0.63 ng/ml were reached. Vaginal absorption of MPA was found to be very rapid with plasma levels between 0.29 and 0.47 ng/ml already three hours after insertion of the IVR. The plasma levels found are lower than previously reported probably due to methodological differences. The plasma levels of MPA are much lower than the d-norgestrel levels found after administration of smaller amounts of d-norgestrel. This is probably explained by differences in compartmentalization of the drugs. The elimination halflife of MPA was found to be about 30 hours which is longer than for d-norgestrel (20 hours).

Comparison of the metabolic effects of two hormonal contraceptive methods: An oral formulation and a vaginal ring I. Carbohydrate metabolism and liver function

A prospective, long-term study was undertaken to compare the metabolic effects of a contraceptive vaginal ring releasing levonorgestrel (about 290 microgram per day) and estradiol (about 180 microgram per day) and a combined oral contraceptive containing 30 microgram ethinylestradiol and 150 microgram levonorgestrel in two groups of women (n = 22 and 20, respectively). An intravenous glucose tolerance test, including determination of the insulin response to glucose, and liver function tests were performed. Both the glucose tolerance and fasting values of glucose were unaltered. The early insulin response to glucose increased by 50 percent in the contraceptive ring roup after one year of treatment, but not in the oral contraceptive group. All other insulin values were unchanged. All liver function values remained within the normal range in all subjects. There was a small significant decrease in alkaline phosphatases in both groups, which is in contrast to the effects of the early combined pills, which could cause an elevation. It is concluded that neither of these two contraceptive methods, the effects of which are predominantly gestagenic, seems to cause impairment of glucose tolerance or hepatic function.

Vaginal Progesterone for Contraception

Silastic vaginal rings impregnated with progesterone (P) or progesterone and estradiol (E) were used in nine women for thirty 21-day cycles to study the effect on ovarian function. The average daily rates of release of P and E from the rings were 2.2 mg/day and 220 microgram/day, respectively. In anovulatory treatment cycles the mean plasma level of P was 0.9 ng/ml. E levels fluctuated in the range seen in normally cycling women due to endogenous E production. In a menopausal woman the E levels increased to 50 to 100 pg/ml during treatment and FSH levels declined. Ovulation occurred in 18 (60%) of the treated cycles, and resulted in one pregnancy. Although the results rule out the use of these rings for contraceptive purposes, they indicate that at higher dosages the Silastic vaginal ring offers a mode of administration of natural steroids to be used in hormonal contraception.

Plasma levels of d-norgestrel and sex hormone binding globulin during oral d-norgestrel medication immediately after delivery and legal abortion.

Abstract To investigate the concentration of d-Norgestrel (d-Ng) in plasma when d-Ng is administered to women with physiologically high concentration of Sex Hormone Binding Globulin (SHBG), 30 μg d-Ng tablets were given daily starting 0–1 day after delivery or abortion. During the first 3–4 days of treatment d-Ng increased to levels 6–8 times higher than found during the same medication to women not recently pregnant. Thereafter, the d-Ng concentration in plasma decreased despite continuous medication in parallel with decreasing levels of SHBG until SHBG reached its normal level after 2–4 weeks. The decrease rate for SHBG after delivery or abortion corresponded to a half life of about nine days. The results indicate an in vivo binding of d-Ng to SHBG and a SHBG influence on the metabolic clearance rate of d-Ng. The in vivo binding of d-Ng to SHBG may have importance in hormonal contraception during lactation.

The plasma concentration of a synthetic progestin, R 2323, released from polysilastic vaginal rings

Abstract The present study was undertaken to study the release of a synthetic progestin, R 2323 (13-ethyl-17-hydroxy-18,19-dinor-17α-pregna-4,9,11-trien-20-yn-3-one), from polysiloxane vaginal rings. Fourteen healthy, normally menstruating women took part in the study. The vaginal rings containing 10,50 or 200 mg of R 2323 were inserted on the first day after menstrual bleeding had ceased and were left in the vagina for three weeks. Blood samples were taken at two-to five-day intervals and the plasma concentration of R 2323 was determined by radioimmunoassay. The results show that the initial release of the steroid is rapid. The highest concentration measured was always in the first sample, usually taken on the first or second day after the insertion. After that the concentrations decreased rapidly.

The effect of weekly administration of an oral progestogen -R 2323- on the ovarian function

Abstract An oral progestogen - R 2323 - was given in the dose of 10 mg as a weekly contraceptive pill. The effect on the ovarian function was followed by measuring the plasma levels of progesterone and estradiol. Seventeen cycles were studied and, in three of these, ovulation occurred. In all other cycles, progesterone and estradiol were depressed to early follicular phase levels. Intermenstrual bleeding or spotting was noticed in all cycles except the ovulatory ones. It is concluded that R 2323 in this dosage probably gives a better contraceptive effect than lower dosages. The occurrence of intermenstrual bleeding and spotting seems to be related to the timing of drug intake.

Ovarian function, bleeding control and serum lipoproteins in women using contraceptive vaginal rings releasing five different progestins

Ovarian function, bleeding patterns and serum lipoproteins were studied in women using contraceptive vaginal rings (CVRs) of dimethyl-polysiloxane impregnated with steroids. The different CVRs were used for about 10 cycles each. The following groups were studied, with the daily steroid dosage given in parentheses. Women using CVRs delivering levonorgestrel (290 micrograms), norethisterone (850 micrograms), medroxyprogesterone acetate (700 micrograms) or megestrol acetate (1.9 mg), all of which were in combination with estradiol (200 ug). Women using CVRs delivering progesterone (5.2 mg). Women taking megestrol acetate orally (15 mg/day) for three weeks. In all women except those using the levonorgestrel CVR, there were indications of incomplete suppression of ovarian activity as shown by elevated levels of progesterone and/or estradiol peaks. Bleeding control seemed to be good with the levonorgestrel CVR and rather poor with the others. Levonorgestrel treatment was associated with a decrease in high density lipoprotein cholesterol (32%) and triglycerides (25%) and a 16% decrease in apolipoprotein A-I. Norethisterone induced a 10% decrease in A-I and a reduction of cholesterol in very low density lipoprotein. All other lipid and apolipoprotein B, A-I and A-II values were unaltered with the administration of the CVRs and with oral megestrol acetate. Levonorgestrel was given in a higher dose than the other progestins, but the absence of effects of the high oral dose of megestrol acetate on the serum lipoproteins indicates that the progesterone-derived progestins in adequate doses probably would not alter the lipoprotein metabolism. Higher doses of progestins are needed to achieve acceptable control of ovarian activity and bleeding patterns than seen with these CVRs.