Pharmacokinetics of different doses of norethisterone oenanthate.

Doses of norethisterone oenanthate of 300, 150, 100 and 50 mg were administered to four groups of subjects. Due to wide intersubject variations there were no statistically significant differences in the pharmacokinetic parameters for the different groups but there were significant correlations between the dose and the mean values for these parameters. There was little difference between the groups in the duration for which ovarian function was suppressed due to the inter-subject variation being greater than the inter-dose effect. The duration of the antifertility action of norethisterone oenanthate cannot be increased by increasing the dose above the standard 200 mg; however, with an injection interval of 60 to 70 days, it seems likely that the dose could be reduced to 150 mg.

PIP: Doses of norethisterone enathate of 300, 150, 100, and 50 mg were administered to 4 groups of subjects. Due to wide intersubject variations, there were no statistically significant differences in the pharmacokinetic paraetmers for the different groups but there were significant correlations between the dose and the mean values for these parameters. There was little difference between the groups in duration for which ovarian function was suppressed due to the intersubject variation being greater than the interdose effect. The duration of the antifertility action of norethisterone enanthate cannot be increased by increasing the dose above the standard 200 mg; however, with an injection interval of 60-70 days, it seems likely that the dose could be reduced to 150 mg.

Some estrogenic effects of two oral contraceptives consisting of norgestrel and two different doses of ethynylestradiol.

Some biological and biochemical effects (i.e. KPI, cervical mucus, SHBG and ceruloplasmin) as well as serum ethynylestradiol and serum norgestrel, following the use of two oral contraceptives containing the same amount of norgestrel (dl-norgestrel 0.5 mg) and either 30 microgram or 50 microgram of ethynylestradiol were compared. There was no difference in the clinical features in either group of patients. There was a statistically significant difference in the levels of unconjugated ethynylestradiol but not in the other biochemical parameters studied. It is concluded that the absence of any such difference might be attributable to the strong antiestrogenic effects of dl-norgestrel.

PIP: This study determined whether a reduction in ethinyl estradiol (EE) dosage from 50-30 mcg was associated with any change in biological features of estrogenic effects in the genital tract (karyopyknotic index, ferning, spinnbarkeit, volume, and clarity of cervical mucus) or biochemical effects (ceruloplasmin and sex hormone binding globulin). 11 healthy women (aged 18-25 years) with normal menstrual cycles were studied for 6 months. Alternate subjects took either Eugynon 30 or 50. There was no correlation of the index with time or with the amount of EE in the pill. Cervical mucus could only be obtained in 1/3 of examinations, and they were of low volume. Spinnbarkeit was never greater than 1 cm; no spinnbarkeit could be demonstrated in 7 specimens. Ferning was not seen in any specimen. Cervical mucus did not vary in character by dosage. Mean EE and norgestrel levels were higher in patients on Eugynon 50. Mean SHBG activity and ceruloplasmin level tended to be higher at 6 months, whereas EE and norgestrel levels diminished. The only values between which there were any statistically significant differences were those of unconjugated EE when the 2 different dosage regimes were compared (P .01). The absence of other effects may result from the strong antiestrogenic effects of dl-norgestrel.

Occurrence of ovulation in women receiving the injectable contraceptive norethisterone oenanthate.

Ovarian function was studied in ten women receiving a single intramuscular injection of 200 mg norethisterone oenanthate. Two of the ten women appeared to ovulate within 60 days of injection and a further four within 90 days. Follicular activity probably not followed by ovulation occurred in five subjects within 60 days of the injection and in a further subject within 90 days. Only one subject showed no evidence of follicular or luteal activity during the course of this study. There was wide variation in the rate at which the administered gestagen was metabolised and no correlation between the rate of metabolism of norethisterone and the return of ovarian function or the ponderal index, height or weight of the subjects.

Plasma levels of norethisterone after single and multiple injections of norethisterone oenanthate.

PIP: To study the likelihood of accumulation of norethisterone enanthate (NE) with repeated administrations, 15 women were given 200 mg NE in a single intragluteal injection (Group 1) and 15 others weere given from 5 to 11 such injections at from 12- to 10-week intervals (Group 2). Blood samples were taken and serum NE concentrations were determined. NE levels fell on a straight regression line when plotted semilogarithmically against number of days postinjection in both groups, but the slopes differed significantly (p .01) with plasma NE decreasing more slowly over time in Group 2. Extrapolated estimations of the time required for NE levels to become undetectable were 107 days for Group 1 and 152 days for Group 2. It is suggested that the steroid metabolic rate may have decrease in Group 2. These findings also offer some rationale for the suggestion that NE be administered at 60-day intervals for the 1st 3 injections and at 90-day intervals thereafter.^ieng

Pharmacokinetics of norethisterone oenanthate in humans.

The pharmacokinetics of a dose of 200 mg NET-OEN were studied after intramuscular injection into nine subjects. Blood levels of NET and NET-OEN increased rapidly, reaching peaks in most subjects within seven days. At all times after injection, serum levels of NET exceeded those of NET-OEN. The half-life of absorption varied from 5.4 to 22.3 days and the half-life of elimination varied from 7.5 to 22.5 days; there was a significant correlation (R = 0.78) between these two half-lives. There were significant correlations between the absorption half-lives and the peak values of NET and NET-OEN, the time to reach peak values and the time for which NET was detectable in serum. In all subjects NET was detectable in the circulation for a longer time after injection (mean value 74 days) than NET-OEN (mean value 43 days). The time for which the two steroids were detectable in the circulation showed a significant correlation with the elimination half-lives but there was no correlation with the peak values attained, the time taken to reach peak values and bioavailability. There was a two-fold variation between the subjects in the bioavailability of NET, less than 5% of the bioavailable NET was released after day 60.

A clinical trial of norethisterone oenanthate (Norigest) injected every two months.

A clinical trial was carried out in which Norigest (200 mg norethisterone oenanthate) was administered by intramuscular injection every 56 days into 383 women studied for 5,521 woman-months of use. No pregnancies occurred. Continuation rates at the end of one, two and three years were 76.6%, 63.7% and 33.8%. Only minor side-effects were recorded. After one year of use, 20.1% women had gained more than 2 kg in weight and 14.8% had lost more than 2 kg. There was marked disruption of the menstrual pattern and irregular bleeding was the major cause of discontinuation. In 38% of the injection intervals analysed, women were amenorrhoeic. Norigest proved an effective and acceptable method of fertility control.

Analysis of a multicentre trial of a new low-dose oral contraceptive in Great Britain.

An oral contraceptive containing D-norgestrel 150 mug. and ethinol oestradiol 30 mug. (Neovletta) was tested in 682 British women during more than 6,000 cycles. The pregnancy rate was 0.2 per 100 woman-years with the exclusion of pregnancies that followed admitted errors of tablet-taking, and 0.8 per 100 woman-years when they were included. 92.2 per cent of cycles were within 28 +/- 3 days. withdrawal-bleeding was missed in 3.3 per cent of cycles. Spotting occurred in 9.3 per cent of cycles and breakthrough bleeding in 5.8 per cent. Total bleeding averaged 4.71 days per cycle. Concurrent symptoms likely to be attributable to the pill were few and only 10.3 per cent of subjects withdrew because of them. It can be concluded that this formulation is extremely well tolerated and highly effective.

Review of the status of oestrogen replacement therapy.

Oestrogen treatment of climacteric disorders, chiefly with formulations based on oestradiol or oestrone, which cause much less metabolic disturbance than synthetic oestrogens, is now widely accepted. Physiological replacement requires a blood production rate approaching 0.5 mg/day. Deleterious effects of oestrogen loss are known, but the appropriate scale of long-term prophylaxis with oestrogens is controversial. Evidence for a risk of endometrial carcinoma from unopposed oestrogen therapy is inconclusive but has focused attention on the concurrent use of progestogens, which is rising rapidly but is at present no more than 10%.

Clinical assessment of a low-oestrogen combined oral contraceptive.

PIP: A 21-tablet oral contraceptive packet containing .5 mg dl-norgestrel and .03 mg estradiol was clinically tested in 1085 women of reproductive age for a total of 7323 cycles. There was 1 pregnancy which may have been due to incorrect tablet use. 98.2% of the cycles fell within a 28-day plus or minus 3-day pattern. 21% of the women had some breakthrough bleeding at some time, but it was confined to 1 cycle in 63% and not more than 2 cycles in 82%. The contraceptive is recommended for general use on the bases of how pregnancy rate, mean intermenstrual bleeding of .54 days per cycle, and the mean total bleeding of 4.87 days per cycle. The hypothesis that an effective combined oral contraceptive using norgestrel as the progestogen can employ as little as 30 mcg of estrogen is supported.^ieng

The absorption of hexachlorophane from Ultralanum ointment.

The application of Ultralanum ointment to adult skin cases has produced levels of hexachlorophane in the plasma comparable with those found in infants who have undergone whole-body washing with hexachlorophane solutions. Clinical evidence of toxicity was not observed, but it is felt that the value of hexachlorophane in topical steroid preparations should be re-appraised, particularly for long-term treatment of large eczematous areas.