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Injectable contraceptive methods are safe, highly efficacious, and commonly used worldwide. Depo-Provera (depot-medroxyprogesterone acetate) is the most commonly used injectable in the United States. It is a convenient, discrete, and low-maintenance method, and is ideal for patients with contraindications to estrogen use and certain medical conditions. In addition, there are many noncontraceptive benefits to Depo-Provera use. Side effects with this method including irregular bleeding, breast tenderness, weight gain, and the impact on bone mineral density should be taken into consideration when prescribing the method. Other injectables such as Mesigyna and norethindrone enanthate are widely used outside the United States.

Objective: It has been reported that the progestin medroxyprogesterone acetate (MPA), but not norethindrone acetate (NETA), inhibits the beneficial vascular effects of post-menopausal estrogen therapy, but their effects on the myocardium are unclear. The goal of this study is to compare the effects of these two progestins on post-ischemic myocardial damage., Methods: Ovariectomized monkeys were fed an atherogenic diet for 18 months while receiving, or not receiving (control, n=15), the monkey equivalent to a woman's dose of 5 mug ethinyl estradiol with either 1 mg NETA daily (n=15) or 2.5 mg MPA daily (n=15). The left anterior descending coronary artery was occluded for 1 h and then released to allow myocardial reperfusion for 4 h. Infarct size was quantified using the histochemical stain triphenyl-tetrazolium chloride. Regional myocardial blood flow was measured by 15 mum neutron-activated microspheres, blood pressure and heart rates with a pneumatic cuff, stroke volume by echocardiography, coronary output by thermodilution and neutrophil accumulation in the myocardium using myeloperoxidase (MPO) activity., Results: The infarct size (area of necrosis/area at risk) was similar between the control group (21+/-3%) and the MPA group (29+/-3%) (P<0.05) but significantly less in the NETA group (3+/-2%) than other groups (P<0.05). The hemodynamic myocardial function and regional myocardial blood values were similar among groups before, during and 4 h after reperfusion (all P-values >0.05). Similarly, there were no treatment effects on MPO activity (P>0.05)., Conclusions: NETA, but not MPA, diminished ischemia-reperfusion injury in estrogen-treated post-menopausal females. The mechanism(s) of this difference remains unclear.

Objective: To measure the effect of 24 months of depot medroxyprogesterone acetate use on bone mineral density compared with oral contraception (pills) and nonhormonal contraception., Methods: Women aged 18-33 years self-selected oral contraception, depot medroxyprogesterone acetate, or nonhormonal contraception (controls). Those selecting pills were randomized to formulations containing either 35 microg ethinyl estradiol and norethindrone or 30 microg ethinyl estradiol and desogestrel. Controls were frequency matched on age and race/ethnicity to hormonal contraception users. Dual-energy X-ray absorptiometry of the lumbar spine (L1-L4) was performed at baseline, 12 months, and 24 months. Percent change in bone mineral density was analyzed by using analysis of covariance, adjusting for age, race/ethnicity, weight-bearing exercise, calcium intake, smoking status, and body mass index., Results: Of the 191 women making up the final sample, 86 used pills, 47 used depot medroxyprogesterone acetate, and 58 used nonhormonal contraception. Women using depot medroxyprogesterone acetate for 24 months experienced, on average, a 5.7% loss in bone mineral density, with a 3.2% loss occurring between months 12 and 24. On average, users of desogestrel pills experienced a 2.6% loss in bone mineral density after 24 months. Bonferroni-adjusted pairwise comparisons demonstrated that bone mineral density changes from baseline to 24 months among depot medroxyprogesterone acetate users differed significantly from changes experienced by either of the pill groups or the control group. Changes in bone mineral density among users of either pill did not significantly differ from each other or from controls., Conclusion: Loss of bone mineral density associated with depot medroxyprogesterone acetate use appears to be linear during the first 2 years of use. Shifts in bone mineral density among pill users were not significant when compared with controls.

Foci of peritoneal fibrosis frequently occur with ovarian neoplasms, especially those of epithelial type, usually in association with foci of metastatic tumor or implants. However, in the absence of the latter, the presence of fibrosis cannot be clearly explained. To find an explanation for this phenomenon, we investigated the development of hormone-dependent peritoneal changes in guinea pigs. Of the 59 guinea pigs studied, 49 received one of the following hormones or hormone analogs: estradiol, diethylstilbestrol (DES), testosterone, estrone, Megace, human chorionic gonadotropin, Norethin, clomiphene, luteinizing hormone, dienestrol, hexestrol, and tamoxifen, over a period ranging from 3 to 9 months. Ten guinea pigs received sterile water (control cases). Multiple peritoneal fibrous plaques 1 to 7 mm in greatest dimension were found in 5 of 7 guinea pigs that received estradiol, 6 of 8 treated with DES, and 2 of 2 that received hexestrol and estrone. The largest lesions (fibrous polyps up to 1.2 cm in greatest dimension) were seen in those that received estrone; however, this hormone was poorly tolerated, as two of the animals that received it died after 1 and 2 months, respectively. Because DES was the best-tolerated hormone, we administered it to five additional guinea pigs for 12 months. All five developed fibrous plaques; three of them also developed peritoneal fibroleiomyomas. We conclude that estrogens can induce the development of fibrous plaques in the peritoneum and when they are administered for a long period of time they also induce the development of smooth muscle nodules. This finding is relevant to understanding the pathogenesis of both fibrous lesions associated with ovarian tumors and peritoneal leiomyomatosis.

Objective: To compare the effect of depot medroxyprogesterone acetate (DMPA) and two types of oral contraceptives (OC) on bone mineral density (BMD) among women 18-33 years of age with those not using hormonal contraception., Methods: Data from 155 women were analyzed. Depot medroxyprogesterone acetate was administered to 33 women; 63 women who chose oral contraception were randomly assigned to receive either a norethindrone-containing pill (n = 28) or a desogestrel-containing pill (n = 35). Fifty-nine women who did not use hormonal contraception served as controls. Lumbar spine BMD was determined using dual-energy x-ray absorptiometry at baseline and after 12 months of contraceptive use. We analyzed method-related percent change in BMD while controlling for body mass index, calcium intake, exercise, and smoking. We had approximately 90% power to detect a 2.5% difference between any two groups., Results: Users of DMPA experienced a mean BMD loss of 2.74% over 12 months compared with controls who sustained a 0.37% loss (P = .01). Users of OCs generally demonstrated a gain (2.33% for norethindrone-containing pills, 0.33% for desogestrel-containing pills), which was different from controls among users of norethindrone-containing pills (P = .01), but not among users of desogestrel-containing pills (P = .99). Observed changes in BMD among DMPA users differed from women who used either type of pill (P < .002)., Conclusion: Depot medroxyprogesterone acetate has an adverse effect on BMD, in comparison with OCs or nonhormonal methods, when used for 12 months. Results must be interpreted cautiously until it is determined whether these effects endure or are reversible.

The influence of progestogens in combination with 17beta-estradiol (E2) on cardiovascular disease remains controversial. This study investigated the effect of norethindrone acetate (NETA) combined with E2 on aortic atherosclerosis. Eighty mature female rabbits were ovariectomized, then fed a cholesterol-rich diet (240 mg/d) for 14 weeks to induce aortic atherosclerosis. They were randomized to four equally large groups for the following 38-week intervention period. One group received placebo, another group oral E2 4 mg daily (E2), and the last two groups oral E2 4 mg daily combined with either NETA 1 mg (E2NETA1) or NETA 3 mg (E2NETA3). The cholesterol intake was reduced to a "maintenance" level of 80 mg/d during the intervention period. Total serum cholesterol and ultracentrifuged lipoproteins were analyzed enzymatically throughout the study. The cholesterol content in the aortic wall was 2.76+/-0.44 micromol/cm2 (mean+/-SEM) in the E2NETA1 group, 1.77+/-0.37 micromol/cm2 in the E2NETA3 group, 5.46+/-0.77 micromol/cm2 in the E2 group, and 7.20+/-0.94 micromol/cm2 in the placebo group (ANOVA P<0.0001). The difference (in the aortic cholesterol accumulation) between the E2 and each of the combined E2/NETA groups was statistically significant (P<0.01) but could only partly be explained by the differences in serum lipids and lipoproteins. In conclusion, NETA enhances the antiatherogenic effect of E2 in cholesterol-fed rabbits. This effect is only partially mediated through changes in serum lipids and lipoproteins.

Objective: To see whether the short-term changes in serum lipid and lipoprotein concentrations induced by postmenopausal estrogen-progestin therapy are maintained in the long term., Methods: Sixty-one healthy postmenopausal women were randomized to either oral therapy (continuous conjugated equine estrogens at 0.625 mg/day with sequential dl-norgestrel at 0.15 mg/day for 12 days each cycle) or transdermal therapy (patches delivering continuous 17 beta-estradiol [E2] at 0.05 mg/day with sequential norethindrone acetate at 0.25 mg/day for 14 days each cycle). Twenty-nine healthy postmenopausal women who did not request therapy served as a reference group. Fasting serum lipid and lipoprotein concentrations were monitored for 3 years., Results: Studied in the estrogen-progestin phase, oral and transdermal therapies reduced serum total cholesterol concentrations by 12.1% (P < .001) and 8.4% (P < .001), respectively, and those of low-density lipoprotein (LDL) by 14.2% (P < .001) and 6.6% (P < .01), respectively. These changes, apparent at 3 months, were maintained over 3 years. Serum triglyceride concentrations fell by 2.5% (P < .05) and 16.4% (P < .01), respectively. These decreases were evident after 6 months in both groups but were maintained over 3 years only in the transdermal group. High-density lipoprotein (HDL) concentrations fell in women given oral therapy (7.8%, P < .05) and transdermal therapy (10.7%, P < .001), as well as in untreated women (7.0%, P < .05)., Conclusions: The potentially beneficial effects of estrogen-progestin therapy on serum total and LDL cholesterol and on triglycerides were maintained over 3 years. Interpretation of the potentially detrimental effects on HDL concentrations was hindered by the changes seen in untreated women.

Objective: To address the hypothesis that multiphasic oral contraceptives (OCs) increase rather than decrease the risk of functional ovarian cysts., Methods: In this single-center, randomized controlled study, women were assigned to a multiphasic pill, a lower-dose monophasic pill, a higher-dose monophasic pill, or nonsteroidal contraception. Forty volunteers were randomized (ten each) to three different pill regimens or to nonsteroidal contraception. During 6 months of treatment, follicular development was measured by vaginal ultrasonography and ovulation was indicated by serum progesterone levels., Results: The relative risk (RR) of developing a follicular structure greater than 30 mm in diameter during a cycle with the higher-dose monophasic pill was 0.5 (95% confidence interval [CI] 0.1-1.9; P = .49) compared with the multiphasic pill. The risk with the lower-dose monophasic pill was comparable to that with the multiphasic pill (RR 1.3, 95% CI 0.5-3.6; P = .56). With the multiphasic pill, the maximum ovulation rate over 60 cycles was 1.7 per 100 cycles (95% CI 0.0-8.9)., Conclusion: This multiphasic pill more closely resembled the lower-dose monophasic pill than the higher-dose monophasic pill in its suppression of follicular development.

Objective: To assess prospectively the effect on bleeding patterns, transformation of the endometrium, and rate of endometrial hyperplasia of transdermal norethisterone acetate when administered sequentially in combination with transdermal estradiol (E2), and to compare it to a regimen using oral medroxyprogesterone acetate., Methods: Two hundred eighteen women were randomized to receive either transdermal E2 0.05 mg/day for 14 days followed by transdermal E2 0.05 mg/day plus transdermal norethisterone acetate 0.25 mg/day for 14 days, or transdermal E2 0.05 mg/day for 25 days with the addition of oral medroxyprogesterone acetate 10 mg/day on days 16-25, followed by a 3-day treatment-free period. Treatment was planned for 13 cycles of 28 days. The subjects kept daily bleeding diaries, and endometrial biopsies were taken before and at the end of treatment., Results: The mean duration of bleeding (regular) induced by the gestagen was 7.33 days in the transdermal gestagen-treated group, which was 1.54 days longer than in the oral gestagen-treated group (P = .0001). The mean cycle day of onset was 25.74. Bleeding was spotting or light in the transdermal group in 77% of the days in which bleeding occurred. When comparing the two groups, there were no differences in the overall mean cycle day of onset or in the intensity of gestagen-induced bleeding. Breakthrough (irregular) bleeding episodes occurred in 42% of the transdermal subjects, lasted a mean of 4.18 days, and were spotting or light in 87% of the days when they occurred. There were no differences between the treatment groups. There was only one case (1.3%) of confirmed simple hyperplasia and five cases of failure of gestagenic transformation of the endometrium in 77 women treated for a mean of 367 days with transdermal gestagen., Conclusion: A transdermal system delivering a combination of E2 and norethisterone acetate for 14 days in sequence with E2 delivered transdermally for 14 days produced bleeding patterns that are clinically acceptable and comparable to those produced by oral medroxyprogesterone acetate given in sequence with E2 delivered transdermally for 25 days. The use of the combination system was not associated with a significant risk of endometrial hyperplasia.

Objective: To assess the efficacy of combining sodium etidronate with low doses of the 19-nor-testosterone progestin norethindrone or using high doses of norethindrone alone as prophylaxis against the vasomotor instability and bone density loss induced by GnRH agonists alone., Methods: Eleven patients enrolled in this randomized study received the long-acting GnRH agonist leuprolide acetate 3.75 mg intramuscularly every 4 weeks for 24 weeks. Six patients (group I) self-administered sodium etidronate 400 mg/day orally for 14 days followed by calcium carbonate 500 mg/day orally for the next 42 days during three 56-day cycles. This regimen was supplemented by norethindrone 2.5 mg/day orally. Five patients (group II) self-administered norethindrone 10 mg/day orally. Two sets of controls were used. Group III consisted of ten previously reported patients who received the same GnRH agonist only. Group IV comprised 12 regularly cycling untreated controls. Bone mineral density, vasomotor symptoms, circulating estrogens, and lipids were assessed serially., Results: The significant vasomotor instability (P < .01) and bone mineral density loss (-4.8 +/- 0.9%; P < .05) experienced by patients in group III was prevented in those in groups I and II despite maintenance of a persistent hypoestrogenic state. Bone density changes in groups I and II were similar to those in untreated controls (group IV). Persistent decreases in high-density lipoprotein (HDL) cholesterol (P = .005) and increases in the low-density lipoprotein-to-HDL ratio (P < .05) were noted only in group II patients receiving supplemental high-dose norethindrone., Conclusion: These preliminary data suggest that the addition of cyclic sodium etidronate in combination with low-dose norethindrone to GnRH agonists is an effective means of ameliorating the hypoestrogenic side effects induced by GnRH agonist alone.

In December 1990, the Food and Drug Administration approved Norplant (Wyeth-Ayerst, Radnor, PA) for general US use. This approval comes during a time period when the number of contraceptors relying on sterilization has risen, echoing known dissatisfaction with other reversible methods. During the past year, data have been presented that refute concern that Norplant may be an abortifacient. Continued estradiol production with development of follicles and ovulation in regularly menstruating women was documented. Ovulatory dysfunction among Norplant users, despite follicular development, was also detailed. Changes in carbohydrate metabolism were confirmed to be clinically insignificant. International development of biodegradable and non-biodegradable implants and 1, 3, or 6 months injectables continues. These injectable and implantable contraceptives promise diversity in contraceptive options to match diversity in contraceptive need and life style.

Objective: We examined the effects of norethisterone and/or mestranol on the pressor response to angiotensin II in 20 healthy men., Methods: Four study protocols were used: I) mestranol 0.08 mg/day for 6 days followed by mestranol plus norethisterone 20 mg/day for 6 days, II) mestranol 0.16 mg/day for 6 days followed by norethisterone alone 10 mg/day for 6 days, III) mestranol 0.24 mg/day followed by norethisterone 20 mg/day for 6 days, and IV) norethisterone 20 mg/day for 6 days. The angiotensin II dose to elicit a 20-mmHg rise in diastolic blood pressure was considered the effective pressor dose. This was determined before each protocol, at the end of the mestranol-alone portion, and at the end of the norethisterone portion. Subjects in study III also underwent measurement of plasma prostanoid levels, plasma renin activity and concentration, and estradiol and progesterone just before each angiotensin II infusion. Subjects in studies I and III underwent measurement of mean platelet volume, complete blood counts, liver function tests, and coagulation factors before each angiotensin II infusion., Results: Whereas mestranol had no apparent effect on angiotensin II pressor response, norethisterone at a dose of 20 mg/day (with or without concurrent mestranol administration) caused a significant decrease in pressor responsiveness to angiotensin II. No changes in plasma prostanoids or renin could be found that would account for the change in pressor response., Conclusion: These findings indicate that the refractoriness to angiotensin II induced by norethisterone was related to its progestogenic properties.

Cardiovascular disease is a major killer in postmenopausal women in the industrialized societies. To investigate the effect of progestogen and 17 beta-estradiol replacement therapy on atherogenesis, we studied 60 cholesterol-fed ovariectomized rabbits for 13 weeks. They were randomly assigned to four groups of 15 rabbits each and received oral treatment with norethisterone acetate, levonorgestrel, 17 beta-estradiol, or placebo. The active treatment groups achieved serum hormone concentrations, which produced physiological effects on the uterus. No significant differences in serum total cholesterol or ultracentrifuged lipoproteins (very low density, intermediate density, low density, or high density lipoproteins) were found between the four groups during the experimental period. There were no significant differences between the progestogen and placebo groups in the aortic accumulation of cholesterol. The estradiol group had only accumulated about half the aortic cholesterol as compared with the placebo group and the progestogen groups (p less than 0.05). The antiatherogenic effect of 17 beta-estradiol was estimated to be equal to a 40-50% reduction in serum total cholesterol. These findings suggest that two commonly prescribed 19-nortestosterone-derived progestogens, which are considered to be "atherogenic," do not affect atherogenesis in cholesterol-fed ovariectomized rabbits, whereas 17 beta-estradiol produces a significant antiatherogenic effect that is independent of lipid metabolism in plasma, possibly the result of a direct action on the arterial wall.

Skin 5 alpha-reductase activity is the major factor influencing the manifestation of androgen excess. Although oral contraceptives have been useful for the treatment of androgen excess, little is known of the independent effects of the various progestins and estrogens on inhibition of skin 5 alpha-reductase activity. We incubated minces of normal genital and pubic skin with physiologic concentrations of 3H-testosterone to assess 5 alpha-reductase activity by its conversion to 3H-dihydrotestosterone. In separate experiments, 5 alpha-reductase activity was assessed before and after the addition of progesterone, medroxyprogesterone acetate, levonorgestrel, norethindrone, 17 beta-estradiol, and ethinyl estradiol. Progesterone, levonorgestrel, and norethindrone demonstrated 97 +/- 5.3%, 47.9 +/- 6.3%, and 59 +/- 4.6% inhibition, respectively, of genital skin 5 alpha-reductase activity at 10(-4) mol/L (P less than .01). Medroxyprogesterone acetate, however, failed to affect 5 alpha-reductase activity at similar doses. Estradiol exhibited 40.8 +/- 14.2% inhibition at 10(-4) mol/L (P less than .01), whereas ethinyl estradiol at concentrations from 10(-8) to 10(-4) mol/L failed to inhibit 5 alpha-reductase activity. We conclude that progesterone and the 19-nor-derivatives inhibit 5 alpha-reductase activity at high doses, whereas medroxyprogesterone acetate does not. Therefore, the 19-nor-progestin component may expand the usefulness of oral contraceptives in the treatment of hirsutism by an inhibitory action on skin 5 alpha-reductase activity.

This study was designed to compare the effects of two low-dose triphasic oral contraceptives (OCs) on glucose tolerance and insulin secretion. Fifty-seven women were randomized to receive OCs containing ethinyl estradiol and either levonorgestrel or norethindrone. Ten subjects using nonhormonal contraception served as controls. Glucose tolerance and insulin secretion were measured at baseline and at 6 and 12 months after an oral glucose stimulus. Both preparations produced a relative hyperglycemia at 6 and 12 months compared with baseline, but within the norms for glucose tolerance. The insulin response, measured in 48 treated and eight control subjects, also increased over 12 months in both treated groups, but the total insulin area was within the range of the reference laboratory. Such minor changes have not been associated with cardiovascular diseases and support the safety of low-dose triphasic preparations.

The effects of conjugated equine estrogen and subsequent cyclical progestogen supplementation on lipoprotein and apolipoprotein A-I levels were investigated in three groups of postmenopausal women. Unopposed conjugated equine estrogen (0.625 mg) lowered total cholesterol 4-8% and low-density lipoprotein (LDL) cholesterol 12-19% below pre-treatment levels in all three groups. Levels of high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I were increased 9-13 and 9-18%, respectively, with unopposed estrogen. The increase in HDL cholesterol was mainly due to increases in the high-density lipoprotein2 (HDL2) subfraction. Addition of medroxyprogesterone acetate, norethindrone acetate, or d,l-norgestrel at doses shown previously to provide protection against endometrial hyperplasia reversed some of the beneficial estrogen effects, reducing levels of HDL cholesterol 14-17%, HDL2 cholesterol 22-37%, and apolipoprotein A-I 11-15% from those obtained with unopposed estrogen. The LDL cholesterol levels fell 12-19% with unopposed estrogen but remained 7-12% below baseline when progestogens were added. These observations demonstrate that after 3 months of treatment, all three progestogens reversed some of the favorable effects of unopposed estrogen on lipoproteins but permitted a continued modest reduction in LDL cholesterol.

A study was designed to determine the effect of a low-estrogen-dosage oral contraceptive on the serum concentration of testosterone-binding globulin (TBG) and total and unbound testosterone in patients with polycystic ovary disease (PCOD). Treatment with norethindrone 0.5 mg and ethinyl estradiol 0.035 mg (Modicon, Ortho) increased the TBG concentration and reduced the unbound serum testosterone concentration.

Synthetic luteinizing hormone releasing hormone (LHRH), 100 mug, was administered intravenously to 29 normal individuals. In male subjects, both baseline and peak LH response values showed minimal variations between subjects. The FSH baseline and response were more variable. In normal females the FSH and LH baseline values and response to LHRH infusion showed greater variation than that seen in male subjects, and this variation correlated with the phase of the menstrual cycle. In perimenopausal women with elevated baseline gonadotropins, the absolute LH peak values were comparable to those seen during the periovulatory period of the menstrual cycle, while FSH baseline and peak values were unmistakably higher than those observed in the normally menstruating women. Three women under gonadotropic suppression by three different drugs were investigated; megestrol suppressed the LHRH response more effectively than either diethylstilbestrol or an oral contraceptive. The LHRH stimulation test reflects only the ability of the pituitary cell to release gonadotropins. In a normal individual, however, some justifiable assumptions can be made regarding the immediate past synthesis and release versus accumulation of pituitary LH.

Previous studies have shown increased mitotic activity in uterine fibromyomas in patients using exogenous hormones. This study has compared the mitotic activity of fibromyomas in three groups of patients. The first group was using a progestin-only preparation (usually depo-medroxyprogesterone acetate). The second group of age-matched controls had never used any exogenous hormone. The third group of patients was using a combined estrogen/progestin oral contraceptive. The results show that patients using a progestin-only preparation have a significantly higher mitotic activity in fibromyomas than patients from the other two groups; results from patients using a combined estrogen/progestin preparation were the same as the controls. The highest count was 39 mitoses/100 high power fields (HPF), but focal areas containing up to 8 mitoses/10 HPF could be found. In none of the fibromyomas examined did the count exceed 10 mitoses/10 HPF, and none showed significant pleomorphism that might have been confused with malignancy.

The effect of norethisterone on bone mineral metabolism was examined in 43 postmenopausal women. A significant decline in serum calcium, phosphate, and alkaline phosphatase in urinary calcium/creatinine ratio and in tubular maximum reabsorption of phosphate was demonstrated. There was no alteration in urinary hydroxyproline/creatinine ratio. The bone mineral content measured over two years by single photon absorptiometry was compared in 20 patients receiving norethisterone and a matched control group receiving placebo. There was significant protection against bone loss in the norethisterone group.

The induction of glycogen deposition as subnuclear vacuoles was found to be a better method in estimating progestational potency of individual progestins than the delay of menses assay. Norgestrel was the most potent progestin in all assays. The progestational potency of oral contraceptives was estimated by multiply potency of individual progestins by their dose. Combination oral contraceptives containing norgestrel were in the mid range of progestational potency because of the relatively higher potency of their progestin. The progestational potency of the norethindrone "mini" pill was compared with that of the norethindrone low-progestogen combination pill and the sequential pill over a 28-day cycle, and no appreciable difference was found.

This study was designed to assess the effect of long-term treatment with three combined oral contraceptives (OC) on the gonadotropin response to LHRH. The release of LH and FSH after a single 50-microgram dose of LHRH was studied from Days 11 to 14 of treatment and Days 2 and 3 after discontinuation of the treatment. The responses were compared with controls during the luteal phase (Days 16 to 19) of the menstrual cycle. LH and FSH baseline levels and release after LHRH injection were markedly depressed in women on OC treatment. The patterns of gonadotropin response after LHRH, however, were similar to the responses during the luteal phase. Following discontinuation of OC treatment, the basal levels of LH and FSH and the response to LHRH continued to be depressed, with a further decrease in the FSH release. These results indicate that treatment with combined OC exert a significant depression on the release of gonadotropins.

A prospective study was undertaken to investigate the carbohydrate and lipid metabolic effects of the oral contraceptive norethindrone. An oral glucose tolerance test was performed before and 1 year after the daily oral administration of 0.35 mg of norethindrome to 31 women. Measurements were made of glucose, insulin, cholesterol, and triglycerides. During the year there was no significant weight change in the women, and the fasting cholesterol values were unaffected by the steroid. The fasting triglycerides decreased as normally occurs in the late postpartum period. There was no change in the blood glucose curve, but there was a statistically significant elevation produced in all of the plasma insulin values. These data suggest that this 19-nor progestogen steroid can affect the peripheral activity of insulin and thus require higher blood levels in order to obtain the same glucose homeostasis.

The authors studied rats pretreated with estrin acetate to determine the renal circulation changes caused by vasopressin and how these changes are influenced by the pressor effect of an antagonist of vasopressin d(CH2)5Tyr(MET)AVP. Abdominal angiography was performed with contrast material administered via a catheter introduced through the common carotid artery up to the aortic arch. After vasopressin administration, a marked spasm occurred in the larger renal arteries, the arteriovenous time increased, and the parenchymal filling became defective. Renal circulation remained undisturbed if the vasopressin antagonist was administered simultaneously. The results suggest that the vasopressin antagonist prevents renal vasospasm after vasopressin administration in rats pretreated with estrin.

The liver extraction of indocyanine green in concentrations of 0.2 mg./kg. and 0.5 mg./kg. in women taking oral contraceptive (norethindrone 2 mg. with mestranol 0.1 mg., and norethindrone 1 mg. with mestranol 0.05 mg.) is reported. No major alteration was noted in the hepatic function with the plasma concentrations of the dye employed. The probability of increased hepatic arterial flow or increased cardiac output due to norethindrone-mestranol combination is noted. The value of indocyanine green in the study of liver dysfunction is stated and its relative sensitivity at various concentrations is mentioned. The use of indocyanine green to predict early hepatic changes in toxemia of pregnancy, especially in those patients with excessive weight gain, is suggested.