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We randomized 32 cycling female Sprague-Dawley rats (82 days old) into experimental and control groups (16 animals/group). Hyperinsulinemia was induced and maintained for 22 days in the experimental group with NPH human insulin (Novolin, Squibb-Novo, Princeton, NJ) as previously described. Controls received an identical volume of vehicle. Fifteen minutes before death, each rat received a sc injection of 100 ng synthetic GnRH (Factrel, Ayerst Laboratories, New York, NY). The mean serum insulin level was significantly higher in the insulin-treated group than in the control group (165 +/- 57 vs. 49 +/- 9 microU/ml; P less than 0.05). The mean final weight also was significantly higher in the insulin-treated group (283 +/- 4 vs. 242 +/- 7 g; P less than 0.001). There were no significant differences in mean final serum levels of testosterone, estradiol, estrone, or androstenedione or in GnRH-stimulated serum levels of LH or FSH. The androstenedione to estrone ratio, however, was significantly lower in the insulin-treated group (2.5 +/- 0.3 vs. 3.4 +/- 0.2; P less than 0.01), suggesting that aromatase activity increased with hyperinsulinemia. Specific [125I]insulin binding to ovarian tissue homogenates was lower in the insulin-treated group (1.7 +/- 0.1% vs. 2.6 +/- 0.6%/0.2 mg protein; P greater than 0.05), suggesting that ovarian insulin receptors tended to down-regulate with hyperinsulinemia. Specific [125I]insulin-like growth factor I [( 125I]IGF-I) binding to ovarian tissue homogenates, in contrast, was significantly higher in the insulin-treated group (13.3 +/- 1.4% vs. 7.2 +/- 0.6%/0.2 mg protein; P less than 0.05), suggesting that ovarian IGF receptors up-regulated with hyperinsulinemia. The affinity of neither [125I]insulin binding nor that of [125I]IGF-I binding changed significantly, with the 50% inhibition point remaining between 2.0 and 5.0 ng/ml for each peptide in both groups. We conclude that hyperinsulinemia increases ovarian [125I]IGF-I binding and stimulates aromatase activity in the rat. These phenomena, if also true in women, could be important factors contributing to the ovarian hyperstimulation observed in various hyperinsulinemic states.

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This study examined the prevalence of both basal and glucose-stimulated hyperinsulinemia and acanthosis nigricans (AN) as well as the relationship between insulin and androgen levels in hyperandrogenic women. Sixty-two women who had an elevation of 1 or more plasma androgen levels were studied. The results in these women, grouped for analysis on the basis of obesity and ovulatory status, were compared to those in 36 control women of similar ages and weights. The anovulatory hyperandrogenic women had the clinical and biochemical features of the polycystic ovary syndrome (PCO). Oral glucose tolerance tests were performed with measurement of glucose, insulin, sex hormone-binding globulin (SHBG), and total and non-SHBG-bound sex steroid levels. AN was present in 29% of the hyperandrogenic women, the majority of them obese. Fifty percent of obese PCO women had AN, but they did not otherwise differ from PCO women lacking this dermatological change. Only women with PCO had significant hyperinsulinemia independent of obesity, and obese PCO women with AN had the highest serum insulin levels. Plasma glucose values during the oral glucose tolerance test were significantly increased in obese PCO women independent of the presence of AN, and 20% of these women had frank impairment of glucose tolerance. Ovulatory hyperandrogenic women had normal insulin levels and glucose tolerance. Obese and nonobese women had different relationships between sex steroid and insulin levels; obese women had significant correlations between insulin and non-SHBG testosterone levels (r = 0.30; P less than 0.05), whereas nonobese women had significant correlations between insulin and FSH (r = 0.40; P less than 0.01), dehydroepiandrosterone sulfate (r = 0.33; P less than 0.05), and SHBG (r = 0.37; P less than 0.05) levels, suggesting that the mechanisms underlying the association between sex steroid and insulin levels are complex. These findings suggest that 1) only women with PCO have hyperinsulinemia independent of obesity; hyperinsulinemia is not a feature of hyperandrogenic states in general; 2) AN is a common finding in obese hyperandrogenic women, particularly those with PCO; 3) only obese PCO women are at risk for impairment of glucose tolerance, independent of the presence of AN, suggesting that the negative impact of PCO and obesity on insulin action is additive; and 4) PCO women with AN can be considered as a subgroup of PCO and do not appear to have a distinct endocrine disorder.

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The availability of norethindrone (NET) in serum was studied in 8 women after daily administration of a combination oral contraceptive pill (MinovlarR) containing 1 mg norethindrone acetate (NETA) and 50 micrograms ethinyl estradiol (EE2) from day 5 to day 25 of the menstrual cycle. The pill was taken daily at 9:30 a.m. after a light breakfast and blood samples were collected at 3 hr on alternate days and at 24 hr on other days after ingestion of the pill. On day 12 or day 15 of the first treatment cycle, serial blood samples were also collected at 1/2, 1, 2, 4, 6, 8 and 24 hr after taking the pill. Serum NET levels were estimated by the radioimmunoassay (RIA) technique. The plot of serum NET concentration versus time (0-24 hr) profile showed a rapid absorption of steroid and a peak NET concentration (18.3 +/- 4.8 ng/ml) reached at 2 hr after ingestion of the pill. By linear regression analysis of data (y = 0.27 + 0.12x; r = 0.95), it was observed that the serum NET level was initially about 1 ng/ml. Thereafter, it increased by 0.12 ng/ml per day up to 3.5 ng/ml by the end of 21 days' treatment with oral pills. The serum NET concentration decay slope fitted a two-compartment open model with an initial rapid decay (half-life of 1.2 +/- 0.1 hr) followed by a slower beta-phase with a half-life of 8.5 +/- 1.5 hr. The study revealed that there was an accumulation of norethindrone in plasma during the treatment period and this suggests the possibility of exploring a reduction in the dose of this preparation so as to achieve the optimum NET concentration for contraception, and thereby avoiding unwanted steroid accumulation in the plasma of women.

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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.

PIP: 6 normally menstruating women were each inserted with a single silastic implant-D releasing (NETA) norethindrone acetate. The levels of endogenous hormones, FSH, LH, E2, and progesterone, were estimated by (RIA) radioimmunoassay procedures in the control and treatment cycles. In addition, the levels of drug in the serum as (NET) norethindrone 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 midcycle peaks, but the progesterone levels were completely suppressed. In the 6th treatment cycle, the serum NET levels were either 0.5 ng/ml or below. The FSH and LH midcycle 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.

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Plasma level of norethindrone (NET) and in vivo release of norethindrone acetate (NETA) were studied in three groups of albino rabbits (5 animals/group) after insertion of one, two and four subcutaneous implants, each containing 40 mg crystalline NETA over a period of 24 weeks. The ratios of the in vivo release rate of steroid were 1, 1.9 and 3.9 in the animals of group I (one implant), group II (two implants) and group III (four implants) respectively. Thus, the in vivo release rate in group II and III showed an increase which was almost twice and four times as great as that of group I. However, the mean ratios of the serum NET levels were 1, 1.2 and 2.4 in animals of group I, II and III respectively. Thus, interestingly, the serum NET level did not show the expected twofold and fourfold increase and lacked correlation with the in vivo release. Although the insertion of multiple implants gives multiple increases in the in vivo steroid release, it does not give rise to a multiple increase in the serum levels of the steroid. It is possible that there is a kind of threshold of steroid concentration in the animals when they are loaded with exogenously administered steroid. When the steroid concentration tends to cross the threshold level, pharmacokinetic or pharmacodynamic processes of the animal work maximum to hold down the steroid level in blood plasma.

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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.

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A single oral dose of micronized oestradiol (1, 2 or 4 mg) was administered to 10 normally menstruating women on the second day of 3 consecutive menstrual cycles. The order in which the 3 doses were given was chosen randomly for each subject. Samples of peripheral blood were withdrawn on 3 occasions (10, 5 and 1 min) before and on 9 occasions (0.37, 0.75, 1.5, 30, 6.0, 12.0, 24.0, 48.0 and 72.0 h) after the ingestion of oestradiol. Oestradiol, oesterone, oestradiol sulphate, oestrone sulphate, testosterone and LH were measured by means of radioimmunoassays in blood plasma on all occasions. The levels of all oestrogens increased significantly following the ingestion of oestradiol, although to a greatly different extent. The largest and most prolonged increase was seen in the case of oestrone sulphate, the levels of which--depending on the dose ingested--were 20-50 times higher than the pre-treatment levels 3 after the ingestion of the oestradiol capsule. The increase of the levels of oestrone sulphate was still significant (P less than 0.001) after 24 h, and following the ingestion of 2 and 4 mg of oestradiol even after 72 h (P less than 0.05). The levels of oestrone and oestradiol sulphate exhibited smaller increases 3 h after ingestion, i.e. 4-10 and 2.5-5 times, respectively, and the plasma levels of oestradiol showed a minor increase only (1.4-1.8 times). The concentration of oestradiol metabolites studied increased proportionally with the dose of oestradiol administered. On the other hand, a clear-cut dose--effect relationship could not be observed between the amount of oestradiol administered and the plasma levels of LH and testosterone. The data indicate that the bulk of perorally administered oestradiol is transformed to oestrone sulphate accompanied by smaller quantities of oestrone and oestradiol sulphate and that the ratios of circulating oestrogens seen after the ingestion of oestradiol deviate considerably from those observed in the normal menstrual cycle.

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PIP: 4 healthy women of proven fertility and normal menstrual cycles were implanted with a single silastic implant D, filled with norethindrone acetate (ENTA) in order to study the effect of continuously released low levels of ENTA (150 mcg/day) on serum levels of follicle stimulating hormone, luteinizing hormone, estradiol-17beta, and progesterone and to assess the site of action. Steroids were measured by radioimmunoassay before the implant and 2-4 cycles during the first 8 months of treatment. Values of steroids prior to implant indicate that all subjects were ovulatory before treatment. During the 1st few months of use, values indicate that ovulation continued unsuppressed. Later cycles demonstrated hormonal disturbances with low serum progesterone during the luteal phase in most of the treatment cycles when compared with controls. Results indicate a gradually increasing suppression on the pituitary-gonadal function.^ieng

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PIP: 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.^ieng

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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.

PIP: 2 uses of prostaglandin analogs (15 methyl PGF2 alpha ester) were studied: effect of vaginal suppositories with the analog on cervical dilation in patients 57-80 days of gestation, and effectiveness of intravaginal use of suppositories containing this analog as a menstrual regulator and early abortifacient. Suppositories containing (each) 1- or 1.5-mg doses of the analog successfully terminated pregnancy of 30-56 days duration in 65-70% of 40 women treated. No significant differences were observed between the 2 dose schedules. In a group of 49 patients studied for the effect of intravaginal administration of PGF2 alpha methyl ester for cervical dilation, cervical dilation of 10 mm or greater was observed after 4 suppositories in all cases. Gastrointestinal side effects were statistically more pronounced in the 1.5-mg vs. 1-mg groups (P.05). Hormonal assays (estradiol-17 beta and progesterone) showed a decline in circulating estradiol-17 beta after vaginal administration of the analog in early pregnancy. Mean levels of 7 cases fell from 2.43 mg/ml-2.1 in 1 hour. These declines were significanly different from pretreatment values (P=.01). Serum progesterone alterations following analog administration were more variable. Whereas the mean level of Estradiol-17 beta fell by 55% after vaginal administration of the abortifacient, mean levels of progesterone fell only 32.7%, mainly because of individual variations. The data indicate a direct action of the analog on the corpus luteum. In addition, the termination of early pregnancy (menstrual regulation) seemed to be caused, partly, by the luteolytic effect of the PGF2 alpha methyl ester as well as by uterine contractions.

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PIP: 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.^ieng

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