Elof D.B. Johansson

Plasma levels of progesterone after vaginal, rectal, or intramuscular administration of progesterone.

Abstract Plasma levels of progesterone were determined after vaginal, rectal, or intramuscular administration of 10 to 100 mg. of progesterone to 35 female volunteers. Progesterone was assayed by a competitive protein-binding technique. The absorption was very rapid by all three routes of administration, usually resulting in peak plasma levels of progesterone within the first 8 hr. after administration. The plasma levels remained elevated for longer periods of time than would be expected from the rapid rate of disappearance described for progesterone. Plasma levels corresponding to those encountered during the luteal phase of the menstrual cycle were attained with an intramuscular injection of 25 mg. of progesterone in oil or four times this dose by vaginal or rectal administration, while an intramuscular dose of 100 mg. resulted in a mean peak level corresponding to mid-pregnancy plasma levels of progesterone.

Effects of progesterone on uterine leiomyoma growth and apoptosis

Uterine leiomyomas appear during the reproductive years and regress after menopause, indicating the ovarian steroid-dependent growth potential. Recently we have found that the use of levonorgestrel-releasing intrauterine system (IUS) is effective in the long-term contraception and management of menorrhagic women with uterine myomas because of a striking reduction in menorrhagia. These clinical experiences prompted us to characterize the effects of progestin on the proliferation and apoptosis of leiomyoma cells cultured in vitro. As epidermal growth factor (EGF) has been shown to mediate estrogen action and play a crucial role in regulating leiomyoma growth, we also investigated the effects of sex steroids on EGF and EGF receptor (EGF-R) expression in leiomyoma cells. In cultures of leiomyoma cells, the addition of either E(2) (10 ng/ml) or P(4) (100 ng/ml) resulted in an increase in proliferating cell nuclear antigen (PCNA) expression in the cells; whereas in cultures of normal myometrial cells, the addition of E(2) augmented PCNA expression in the cells, but P(4) did not. Immunoblot analysis revealed that leiomyoma cells contained immunoreactive EGF and that P(4) treatment resulted in an increase in EGF expression in the cells. In contrast, E(2) treatment augmented EGF-R expression in cultured leiomyoma cells, but P(4) did not. These results indicate that P(4) up-regulates the expression of PCNA and EGF in leiomyoma cells, whereas E(2) up-regulates the expression of PCNA and EGF-R in those cells. It is, therefore, conceivable that P(4) and E(2) act in combination to stimulate the proliferative potential of leiomyoma cells through the induction of EGF and EGF-R expression. We also found that Bcl-2 protein, an apoptosis-inhibiting gene product, was abundantly expressed in leiomyoma relative to that in normal myometrium, suggesting that the abundant expression of Bcl-2 protein in leiomyoma cells may be one of the molecular bases for the enhanced growth of leiomyoma relative to that of normal myometrium in the uterus. Furthermore, Bcl-2 protein expression in leiomyoma cells was up-regulated by P(4), but down-regulated by E(2). Therefore, it seems likely that P(4) may also participate in leiomyoma growth through the induction of Bcl-2 protein in leiomyoma cells.

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.

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.

NORPLANT CONSENSUS STATEMENT AND BACKGROUND REVIEW

This review has highlighted the attributes of a very important new method of contraception. The signatories to this document agree that, with the provision of appropriate information and instruction for the user, Norplant is a good contraceptive choice to be made available worldwide in family planning programs that have the resources for appropriate training and counseling. The signatories to this document are acting in their own personal capacity and not as representatives of any particular organization.

Observations on the Antigenicity and Clinical Effects of a Candidate Antipregnancy Vaccine: β-subunit of Human Chorionic Gonadotropin Linked to Tetanus Toxoid* †

Observations on the antibody response and clinical effects of injection of purified beta-subunit of human chorionic gonadotropin covalently linked to tetanous toxoid were made in 15 healthy young women who had previously undergone tubal ligation. Antibodies detectable by radioimmunoassay were found in 14 of the women. Clinical surveillance and immunologic, hematologic, and biochemical tests indicated excellent local and systemic tolerance to the antigen. No significant adverse effects on menstrual function, endocrine status, or health were found.

d-Norgestrel concentrations in maternal plasma, milk, and child plasma during administration of oral contraceptives to nursing women

In order to correlate plasma and milk concentrations of d-norgestrel (d-Ng) in lactating women, three oral contraceptives, containing different amounts of this synthetic gestagen, were given to 15 fully lactating women, starting two months post partum. Plasma and milk samples were collected according to a special schedule. d-Ng concentrations in plasma and milk were measured by radioimmunoassay. When d-Ng was measured in milk, extraction was performed with petroleum ether and in the radioimmunoassay an internal standard was used. This method is evaluated in the present paper. The plasma: milk ratio of d-Ng was found to be about 100:15 and the amounts of d-Ng transferred with 600 ml. of milk per day were calculated to be 0.3 an 0.15 microgram with daily intakes of 250 and 150 microgram of d-Ng, respectively, corresponding to about 0.1 per cent of the given dose. When the women received 30 microgram of d-Ng daily, no d-Ng could be detected in the milk. In three of the breast-fed children the d-Ng concentration in plasma was measured. This concentration was found to be in the same range as would be expected after oral d-Ng medication to adults, allowing for body weight differences, indicating that d-Ng is metabolized and is not accumulated in the baby.

PLASMA LEVELS OF OESTRONE, OESTRADIOL AND GONADOTROPHINS IN POSTMENOPAUSAL WOMEN AFTER ORAL AND VAGINAL ADMINISTRATION OF CONJUGATED EQUINE OESTROGENS (PREMARIN)

Peripheral plasma from five postmenopausal women was analyzed for oestrone and oestradiol during 48 hours after administration of 1‐25 mg Premarin (conjugated equine oestrogen) orally and vaginally. Oestrone and oestradiol were separated on columns of Sephadex LH 20 before radioimmunoassay. Administration of 1.25 mg of Premarin produced a marked increase in plasma oestrone levels and 24 hours after treatment the oestrone levels were still above follicular phase levels. The plasma pattern of oestradiol was similar but the elevation was less pronounced. The biological activity of Premarin as indicated by depressed gonadotrophin levels was similar with the intravaginal and oral routes of administration.

Plasma levels of levonorgestrel in women during longterm use of Norplants.

Levonorgestrel plasma levels were determined by a specific radioimmunoassay in a group of 110 women at various intervals between 1 and 60 months following implantation of six silastic capsules containing levonorgestrel (Norplant). The implants were placed subdermally in the anterior aspect of the forearm. Blood samples were taken twice a week for six consecutive weeks in each subject. Blood drawn from the antecubital vein ipsilateral to the implant site contained two to three times more levonorgestrel than contralateral samples. Average systemic plasma levels represented by contralateral samples ranged from 0.35 +/- 0.03 to 0.29 +/- 0.02 ng/ml (Mean +/- S.E.) in the first and fifth year, respectively. The difference between these values is statistically significant at the 6% level. The results of the regression analysis of individual levels suggest that the decline observed throughout the first five years is mainly due to an early decrease taking place in the first two years. When the sampling period was repeated in the same subjects two or three times 10 to 24 months apart, no significant difference was found. A significant negative correlation was found between plasma levonorgestrel levels and body weight and body surface. The data indicate that the contraceptive efficacy of Norplants during the first five years of use is associated with sustained release of levonorgestrel and is in keeping with the estimated life span of Norplants of seven years.

Ethinyl estradiol in human milk and plasma after oral administration

Abstract In order to estimate the concentration of ethinyl estradiol in milk, four fully lactating women were given an oral contraceptive containing 50 μg ethinyl estradiol + 4 mg megestrol acetate, starting two months after delivery, and four women who wanted to stop nursing after a lactation period of 6–18 months were given one tablet of 500 μg ethinyl estradiol. Milk and blood samples were taken simultaneously after 3, 7, 11 and 23 hours. The concentration of ethinyl estradiol in plasma and milk were estimated by radioimmunoassay. The method for the assay of ethinyl estradiol in milk is evaluated in this paper. The concentration of ethinyl estradiol in milk from the women taking the oral contraceptive was below the detection limit of the assay. In the women taking 500 μg of ethinyl estradiol, the plasma:milk ratio of ethinyl estradiol was found to be about 100:25. The relative dose of ethinyl estradiol ingested by a fully nursed baby, when its mother takes an oral contraceptive containing 50 μg of ethinyl estradiol, has been calculated to be about 10 ng per day, which is 0.02 per cent of the dose given to the mother.