Vimla Laumas

Radioactivity in the breast milk of lactating women after oral administration of 3H-norethynodrel.

In an investigation of the excretion of oral contraceptives in the milk of lactating women, tritiated norethynodrel (the progestin component of Enovid) was administered after 2 days of Enovid to 4 patients with stillbirths. An average of 1.1% (range .45-1.52%) of the radioactive norethynodrel was excreted in the breast milk; on the basis of 5.0 mg of norethynodrel per Enovid tablet this amounts to an excretion of 55 mg of the progestin and its metabolites. Since such products could affect the infant, caution is urged in administration of oral contraceptives during lactation.

Effect of 15(S)15-methyl-PGF2α-methyl ester vaginal suppositories on circulating hormone levels in early pregnancy

Intravaginal administration of 15-methyl-PGF2alpha-methyl ester in the form of suppositories terminated pregnancy in 70 percent of the cases whose last menstrual periods ranged from 35 to 56 days. The use of these suppositories in 49 patients, between 57 to 80 days of gestation, dilated the cervix by 10 mm or more, in one hundred percent of the cases. A decrease in circulating levels of estradiol-17beta and progesterone was observed following 15-methyl-PGF2alpha administration. The mean estradiol-17beta levels declined by about 55.9 percent at 9 hours whereas, the corresponding fall in progesterone was 32.7 percent. This was indicative of a direct action of 15-methyl-PGF2alpha on the corpus luteum. The vaginal use of 15-methyl-PGF2-alpha-methyl ester suppositories thus appears to be a promising method for the termination of early pregnancy and for pre-operative cervical dilatation. The termination of early pregnancy appears to be partly due to the luteolytic effect of 15-methyl-PGF2alpha besides stimulating uterine contractions.

Hormonal changes in patients undergoing therapeutic abortion with prostaglandin F2α, 15(S)-15-methyl-prostaglandin F2α and hypertonic saline

Abstract Intra-amniotic PGF 2α and extra-amniotic 15(S)-15-methyl-PGF 2α (15-methyl-PGF 2α ) when administered to women for induction of abortion decreased the serum progesterone, HPL and estradiol-17β levels. These hormones, estimated by specific radioimmunoassays, showed a greater and somewhat faster decline with extra-amniotic 15-methyl-PGF 2α than with intra-amniotic PGF 2α . Interestingly, in one case (FMP) where 15-methyl-PGF 2α failed to terminate pregnancy, no change in the hormonal patterns were observed. Similarly, in another case (CP) where two doses of PGF 2α failed to terminate pregnancy, no change in the estradiol level was observed. However, after the third dose, a sharp fall in the estradiol level occurred which was followed by abortion. On the other hand, intra-amniotic hypertonic saline caused a sharp fall in the estradiol level only. The decrease in progesterone and HPL by saline was rather slow and inconsistent as compared to prostaglandins. The contribution of the changes in serum hormonal levels to the understanding of the mechanism of action of these abortifacients is discussed.

RADIOIMMUNOASSAY OF NORETHINDRONE : SERUM LEVELS OF NORETHINDRONE IN LACTATING WOMEN AFTER INSERTION OF A SINGLE SILASTIC IMPLANT RELEASING NORETHINDRONE ACETATE

A specific radioimmunoassay was developed for the estimation of norethindrone levels in the serum of lactating women. A conjugate of norethindrone-3-BSA was synthesized and antiserum raised against it in rabbits. The antiserum showed high affinity (1.5 x 10(9)M/L) and titer and was specific. The sensitivity of the assay was 125 pg/ml serum. Serum levels of norethindrone were estimated in 25 lactating women, inserted with subdermal implant releasing about 150 ug of norethindrone acetate daily. The norethindrone levels were initially high in the first two months. From there onwards the levels of norethindrone remained constant with an average value of 1.0 ng/ml up to six months. These values were comparable to those obtained in non-lactating women. Thus, lactation does not seem to alter or affect the release of norethindrone acetate from the subdermal implant or its metabolism.

Distribution and uptake of radioactivity in rat tissues after a single injection and constant infusion of 3H-norethynodrel☆

Abstract The uptake of 3 H-norethynodrel in the neural, genital, and other tissues of the female rat after a single injection and constant infusion has been studied. The results show that radioactivity due to norethynodrel and its metabolites is rapidly taken up in these tissues. Subsequently, the disappearance of radioactivity from these tissues showed an initial rapid disappearance followed by a slow disappearance. Maximal uptake in the neural and genital tissues is attained within 5 minutes of the single injection. A higher uptake of radioactivity was found in the ovary compared with the uterus by both single injection and constant infusion techniques. The possibility of a direct action of norethynodrel on the ovary is considered. The uptake of radioactivity in the uterus and ovary was 5.8 × 10 −8 M, and 4.0 × 10 −7 M, respectively. There was a low uptake in the hypothalamus and the other brain areas. These results are discussed in the light of available information on the mode of action of oral gestogens.

The possibility of estrogenic activity in the human and goat milk after administration of oral gestagens

Abstract Estrogenic activity in the milk of eleven women and five goats was tested after the administration of oral gestagens. Administration of Enovid resulted in the excretion of estrogenic activity in the milk of two out of the three subjects tested. Estrogenic activity was demonstrated in the milk of two women after the oral administration of norethynodrel while in four women no activity could be detected. In the case of goats, however, after the administration of norethynodrel, estrogenic activity was detected in the milk of three out of four goats. No estrogenic activity was found when progestogens which are derivatives of 17α-acetoxy progesterone were administered to women and goats. These results suggest that a judicious selection of oral gestagens for fertility control be made if administered during lactation.

Uptake and disappearance of 1α-3H-chlormadinone acetate in various tissues of the rat

Abstract The uptake and disappearance of 1 α- 3 H-chlormadinone acetate (CAP) in various tissues of the rat have been studied after a single injection and a constant infusion. CAP is rapidly taken up by the neural and genital tissues. The disappearance curve showed an initial rapid fall followed by a slow disappearance: The slow disappearance part of the curve indicates some retention of the CAP and its metabolites in these tissues. The molar concentration of the steroid and its metabolites in the uterus and ovary was 2.4 × 10 −7 M and 6.6 × 10 −7 M, respectively, after a constant infusion for five hours. The uptake in the ovary was higher than that in the uterus indicating the possibility of direct action of CAP on the ovary. Compared with neural and genital tissues, mammary gland and fat showed a much higher uptake of CAP. The molar concentration of CAP in the mammary gland was 3.9 × 10 −6 M at 120 minutes, and there was evidence of retention of CAP in the mammary gland. The significance of these findings in the action of CAP is discussed.

Priming effect of norethynodrel on the uptake of [6,7-3H]-estradiol in the mouse uterus

Abstract The priming effect of 0.01, 0.1, 1.0, 5.0, 10 and 50 μg of norethynodrel for different intervals of time on the uptake of [6,7-3H]-estradiol by the mouse uterus has been studied and compared with the priming effect of 0.01 μg estradiol on this uptake. Norethynodrel in doses up to 5.0 μg produced stimulation of [3H]-estradiol uptake while pre-treatment with 50.0 μg norethynodrel caused an inhibition in the uptake of [3H]-estradiol. Maximal stimulation of the [3H]-estradiol uptake was observed after 4 h of the priming dose of 1.0 μg of norethynodrel which is comparable to the priming effect of 0.01 μg estradiol. The dose-dependent stimulatory and inhibitory effects of norethynodrel on [3H]-estradiol uptake by the uterus may have important implications in the mode of action of this oral progestin.

Correlation between the serum norethindrone (NET) levels attained after insertion of a silastic implant releasing norethindrone acetate and the endogenous hormones particularly progesterone

Six normally menstruating women were inserted each with a single silastic implant-D releasing norethindrone acetate (NETA). The levels of endogenous hormones, FSH, LH, E2 and progesterone, were estimated by radioimmunoassay (RIA) procedures in the control and treatment cycles. In addition, the levels of drug in the serum as norethindrone (NET) which is a major metabolite of NETA were also estimated by RIA procedures in the treatment cycles. In all, 12 treatment cycles were studied. In the initial treatment cycles (1st/2nd or 3rd), the serum NET levels were either 1 ng/ml or above. The LH and FSH showed either normal or suppressed mid-cycle peaks, but the progesterone levels were completely suppressed. In the sixth treatment cycles, the serum NET levels were either 0.5 ng/ml or below. The FSH and LH mid-cycle peaks were lower but distinct while the luteal progesterone levels were of normal ovulatory type. These studies lead us to the conclusion that a serum level of NET of the order of 1 ng/ml is required to bring about suppression of luteal progesterone, either as a result of direct action on the ovary or through suppression of pituitary gonadotropins. When the serum level falls to 0.5 ng/ml or below, the suppressive effect is removed and ovulatory pattern of progesterone returns.

Disappearance of [1α-3H]-chlormadinone acetate in the plasma and red cells of rhesus monkey

The half-life and metabolic clearance rate of chlormadinone acetate in 4 rhesus monkeys was computed after iv injection. Chlormadinone was analyzed as total, free, and conjugated radioactivity, and as recrystallized chlormadinone acetate. 55.0 mc Ci, 222 mc Ci/mg was injected iv in 5 ml ethanolic saline. There was an initial rapid disappearance, half-life 68 minutes, and a slower disappearance, half-life 35.1 hours. These half-lives are much longer than those of estradiol and progesterone, but are shorter in monkeys than in women. The metabolic clearance rate of chlormadinone acetate was 102.6 liters/day. The half-life in red cells of 1 monkey was similar to those seen in plasma, but the amount of chlormadinone acetate was much less.