Gonadotropin-releasing hormone agonist plus add-back sex steroids to reduce risk of breast cancer.
Explore the source record for details and available documents.
Breast Neoplasms↗
Biomedical subjects
D Shoupe
Publications and source records attributed to D Shoupe.
GnRH agonists as contraceptive agents: predicted significantly reduced risk of breast cancer.
Gonadotrophin-releasing hormone agonists (GnRHAs) were investigated as contraceptive agents from the late 1970's to the mid-1980's. They were abandoned as they appeared to offer no advantage over conventional combination-type oral contraceptives (COCs). This conclusion appears to be incorrect. We propose here a contraceptive regimen of a depot formulation of a GnRHA plus add-back estrogen and intermittent progestogen. The dose of add-back sex-steroids is substantially less than that in COCs; this reduction in sex-steroids should lead to a major reduction in lifetime breast cancer occurrence.
Bone and Bones↗
The significance of bleeding patterns in Norplant implant users.
The purpose of this study was to examine the bleeding patterns of 234 Norplant users during 5 years of use and to identify the bleeding patterns of users who conceived. During the first year of use, 26.6% of users had regular bleeding cycles, 66.3% had irregular cycles, and 7.1% were amenorrheic. By the fifth year of use, 62.5% of users had regular cycles, 37.5% had irregular cycles, and none had amenorrhea. Of the ten users who became pregnant, eight had regular menstrual cycles in the 6 months before the diagnosis of pregnancy, one had an irregular pattern, and one did not keep a bleeding record. None had amenorrhea. The 5-years cumulative pregnancy rate for patients with regular cycles was 17.4%; this was significantly higher (P less than .05) than the 5-year cumulative rates of 4.4% in users with irregular cycles and 0% in users with amenorrhea. This study indicates that during the first year of Norplant use, only 26.6% of users have regular cycles, but after the first year, 50-60% of users develop regular cycles. The bleeding patterns of women using Norplant improve after the first year of use, and those with regular cycles are at greatest risk for method failure.
Contraceptive Agents, Female↗
Contraceptive options for the gestational diabetic woman.
Explore the source record for details and available documents.
Contraceptives, Oral↗
Characteristics of ovarian follicular development in Norplant users.
Daily transvaginal ultrasound (US) scanning of the ovaries to assess follicular development and daily blood sampling were performed on 19 Norplant (Leiras, Turku, Finland) subdermal contraceptive implant users who had regular menstrual cycles and on 10 normally cycling women. Three groups were identified in the implant users based on US finding. Six (31.6%) of the implant users had US findings that were consistent with a normal ovulatory pattern. However, their mean peak luteinizing hormone levels and peak midluteal phase progesterone (P) levels were significantly lower than control values. Eleven (57.9%) users had persistent follicles, and 2 users (10.5%) had no follicular development. These data suggest that after 2 to 4 years of use, about one third of Norplant users with regular bleeding patterns may ovulate but most have deficient luteal P levels. In this small study, the presence of persistent follicular enlargement in implant users was common.
Contraceptive Agents, Female↗
Postmenopausal hormone replacement with a combination estrogen-progestin regimen for five days per week.
A group of 15 postmenopausal women who had not recently received estrogen replacement were enrolled in a study during which they received 0.625 mg of conjugated equine estrogen and 2.5 mg of medroxyprogesterone acetate daily from Monday through Friday of each week for six months. No treatment was given on the weekend. Endometrial biopsy specimens at the end of therapy revealed minimal growth of glands and stroma and a low mean mitosis count. Of the 12 women who completed the trial, 5 were completely amenorrheic, and only 4 of the 15 bled beyond the second month of treatment. Of those four, two spotted for only a few days. In the 12 women who completed the trial there was a significant increase in high density lipoprotein cholesterol and a nonsignificant lowering of low density lipoprotein cholesterol. The results of this study indicate that comparative trials between this regimen and one in which the two drugs are given daily for seven days a week are warranted.
Adult↗
Effect of low-dose oral contraceptives on carbohydrate and lipid metabolism in women with recent gestational diabetes: results of a controlled, randomized, prospective study.
Women with recent gestational diabetes mellitus were randomly assigned to one of two low-dose oral contraceptives to evaluate the effect of low-dose oral contraceptives on carbohydrate and lipid metabolism. A cohort of similar women requesting a non-oral-contraceptive method served as controls. The two oral contraceptives studied were ethinyl estradiol (0.035 mg)-norethindrone (0.40 mg) and ethinyl estradiol (0.030 to 0.040 mg)-levonorgestrel (0.050 to 0.125 mg). A 75 gm, 2-hour oral glucose tolerance test and a fasting lipid profile (total cholesterol, triglyceride, high- and low-density lipoprotein cholesterols) were performed at entry, after 3 months, and after 6 to 13 months of treatment. The prevalence of diabetes at 6 to 13 months (27/156 patients) was not significantly different between groups (non-oral-contraceptive group, 17%; ethinyl estradiol-norethindrone, 15%; ethinyl estradiol-levonorgestrel, 20%). When examined by prior gestational diabetes mellitus class, diabetes mellitus was present in 7% of prior class A1 and 29% of women with prior class A2 disease (p less than 0.001). Mean cholesterol and low-density lipoprotein cholesterol levels were significantly improved in all three groups at 3 months and at 6 to 13 months, whereas triglycerides remained unchanged. There were no differences in cholesterol, low-density lipoprotein cholesterol, or triglycerides levels between the groups. After 6 to 13 months, there was a significant increase in high-density lipoprotein cholesterol in the ethinyl estradiol-norethindrone group compared with the ethinyl estradiol-levonorgestrel and non-oral-contraceptive groups.
Adult↗
Antiprogestin treatment decreases midluteal luteinizing hormone pulse amplitude and primarily exerts a pituitary inhibition.
Mifepristone (RU 486), a synthetic steroid with antiprogesterone receptor activity, was given with and without naloxone hydrochloride to six women in the midluteal phase to investigate the role of progesterone in the modulation of endogenous opioid activity and the secretion of luteinizing hormone and cortisol. Subjects were evaluated during four sequential monthly admissions during which multiple blood samples were obtained every 15 minutes for 8 hours. Patients were studied during a baseline cycle, after administration of RU 486 alone (100 mg/day), naloxone with RU 486, and naloxone alone. After administration of RU 486 there was a significant decline in total luteinizing hormone secretion (p less than 0.01) and luteinizing hormone pulse amplitude (p less than 0.05), but compared with baseline there was no significant change in luteinizing hormone pulse frequency. After infusion of naloxone there was a significant increase in mean luteinizing hormone values (p less than 0.05) and luteinizing hormone pulse frequency (p less than 0.01) but no change in pulse amplitude. There was no significant difference in mean luteinizing hormone values or luteinizing hormone pulse amplitude and frequency between administration of RU 486 and naloxone plus RU 486. Administration of naloxone alone, RU 486 alone, and RU 486 plus naloxone caused a significant increase in cortisol as compared with baseline cycles (p less than 0.05). These data further support the notion that progesterone is important in the control of luteinizing hormone secretion and suggest that progesterone may primarily influence luteinizing hormone pulse amplitude and pituitary release of luteinizing hormone during the luteal phase.
Adult↗
Predictors of failed attempted abortion with the antiprogestin mifepristone (RU 486).
The experience of 271 patients who received mifepristone (RU 486) in experimental protocols from July 1984 to January 1989 was analyzed by logistic regression methods. The regimen used was the strongest predictor of failure, followed by Quetelet's index and initial beta-human chorionic gonadotropin level. The relative risk of failure was 2.3 times with 7-day regimens and 6.3 times with the other regimens that obtained with regimens of 600 mg given once or twice. The relative risk of failure increased with increasing Quetelet's index; women in the top quartile were 2.9 times more likely to fail to abort than were women in the bottom quartile. The risk of failure increased with increasing initial beta-human chorionic gonadotropin level; those with an initial level greater than 19,800 mIU/ml were 2.8 times more likely to fail to abort than were women with an initial value less than or equal to 6350 mIU/ml. Body mass appears to influence the likelihood of abortion with mifepristone.
Abortifacient Agents↗
Long-term contraception with the levonorgestrel 20 mcg/day (LNg 20) and the copper T 380Ag intrauterine devices: a five-year randomized study.
An intrauterine device, releasing approximately 20 micrograms/day of levonorgestrel (LNg 20), used by 1124 women, was studied in a randomized trial of five years duration in comparison with the Copper T, model TCu 380Agm in 1121 women. At five years, the gross cumulative pregnancy rate of 1.1 +/- 0.5 per 100 among users of the LNg 20 devices was not significantly different from the rate of 1.4 +/- 0.4 per 100 experienced by users of the Copper T 380Ag. The steroid-releasing IUD had significantly higher termination rates for expulsion and amenorrhea, a significantly lower termination rate for other menstrual problems and pain, and a lower continuation rate. The five-year continuation rate among women using the TCu 380Ag was 40.6 per 100 as compared with that of 33.0 per 100 among women randomized to the LNg 20 device (P less than .001). Terminations attributed to amenorrhea with the LNg device primarily account for differences in continuation. These two intrauterine devices are the most effective long-term, reversible IUDs yet reported in the literature. No other contraceptive methods have exhibited such low long-term pregnancy rates in randomized comparative trials.
Adolescent↗
Norplant: subdermal implant system for long-term contraception.
Norplant offers long-term contraception through the use of subdermal capsules filled with levonorgestrel. The six capsules are implanted in the inside part of the upper arm. The levonorgestrel is released from the capsules gradually, providing contraception for about 5 years. The primary mechanism of action of Norplant is suppression of ovulation. Studies have shown a pregnancy rate of 0.6/100 woman-years after 1 year and a cumulative rate of 1.5/100 woman-years at 5 years. Principal side effects are irregular menstrual bleeding and headaches. No changes in carbohydrate metabolism, blood coagulation, or liver function have been reported. Lipid levels have decreased 5% to 15%. After removal of Norplant, fertility returns rapidly, and there have been no adverse effects on infants. Norplant is currently approved in 12 countries; clinical trials are being conducted in 37 countries.
Administration, Cutaneous↗
Correlation of endometrial maturation with four methods of estimating day of ovulation.
Dating of maturity of the endometrium by histologic examination was correlated with four methods of ovulation detection in 13 cycling parous women. Histologic dating was assessed independently by two pathologists and correlated with the postovulatory duration as determined by daily transvaginal ultrasound scanning, serum LH measurements, basal body temperature (BBT), and subtraction of 14 days from the onset of menses. In addition, progesterone and estradiol (E2) were measured in daily serum samples. Dating of the endometrial biopsy was highly correlated (P less than .002) with the day of ovulation as determined by ultrasound, and was found to be within 2 days of the correct postovulatory day on evaluation of 25 of 26 (96.1%) of the interpretations. The accuracy of dating using the LH surge was 84.6% (22 of 26 interpretations), and with the BBT thermogenic shift was 76.9% (20 of 26 interpretations). However, dating of the endometrium was within 2 days of the correct day in only 17 of the 26 interpretations as determined by subtracting 14 days from the onset of the subsequent menses. The accuracy of dating was significantly better correlated (P less than .025) with days from ovulation as determined by ultrasound than as calculated from the onset of menses. There was a significant correlation between endometrial dating and the amount of progesterone (P less than .01) and E2 (P less than .01) secreted from the day of ovulation, as determined by transvaginal ultrasound, to the day of biopsy. These data confirm a strong correlation between endometrial dating and ovarian hormone secretion during the postovulatory phase.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Response to the antiprogestagen RU 486 (mifepristone) during early pregnancy and the menstrual cycle in women.
RU 486 has wide potential utility as an abortifacient drug when used within the first 6 weeks of pregnancy and has the ability to induce an abortion in about 80% of subjects. Administration of low doses of prostaglandins together with RU 486 increases the success rate. It is possible that alterations in metabolism of RU 486 may explain non-responsiveness to the drug in some women. Mid-luteal phase administration of RU 486 produces bleeding within 72 h and in one-third of subjects there was luteolysis with decrease in serum FSH, oestradiol and progesterone concentrations. Administration of RU 486 in the late luteal phase does not disturb menstrual cycle length, bleeding patterns, ovulation, or hormonal parameters in treatment or posttreatment cycles. However, the drug alone cannot be used as a 'menses regulator' or 'once monthly pill' since some pregnancies do continue. Possibly the efficacy of RU 486 may be enhanced when it is combined with prostaglandins or other agents. Administration of RU 486 in the follicular phase blocks ovulation, delays the LH surge, and is associated with low concentrations of oestradiol. This is presumably the result of gonadotrophin inhibition.
Abortion, Induced↗
Early abortion with a single dose of the antiprogestin RU-486.
RU-486 is a synthetic progesterone antagonist that is abortifacient in early pregnancy. This trial evaluated the effectiveness and safety of a single 600 mg oral dose given to 50 healthy women less than or equal to 49 days from their last menstrual period. Efficacy was inversely related to the initial beta-subunit of human chorionic gonadotropin level, ranging from 100% at less than 5000 mIU/ml to 81% at greater than 20,000 mIU/ml (p less than 0.05). Uterine bleeding was the most serious side effect. However, the mean change in the hemoglobin value 14 days after treatment was -0.4 gm/dl, and no patient required blood transfusion. This regimen appears to be simple, effective, and safe.
Abortifacient Agents↗
A randomized comparison of nonoral estradiol delivery in postmenopausal women.
We compared the transdermal and subdermal routes of estrogen administration with respect to the constancy of estrogen delivery and metabolic effects. Twenty postmenopausal women were randomized to receive either two 25 mg estradiol pellets subdermally (n = 10) or a 0.1 mg estradiol transdermal patch twice weekly (n = 10). Blood was sampled at 0, 2, 4, 6, 8, 12, 24, and 72 hours and 1, 2, 4, 8, 12, 16, 20, and 24 weeks (fasting samples at 0, 12, and 24 weeks), and a fasting urine was obtained after diuresis at 0, 12, and 24 weeks. In a 72-hour profile, serum estradiol levels (mean +/- SE) were highest at 24 hours (179 +/- 20 pg/ml) and fell to 139 +/- 16 pg/ml at 72 hours in the pellet group. In the patch group, estradiol levels rose rapidly to 152 +/- 33 pg/ml at 4 hours, remained relatively constant over 8 hours, and fell to 46 +/- 10 pg/ml at 72 hours. At 1 week, estradiol levels in the pellet group were 113 +/- 12 pg/ml and remained relatively constant for 24 weeks. In contrast, estradiol levels in the patch group were 52 +/- 11 pg/ml at 1 week and then varied widely until 24 weeks, when the levels were 89 +/- 26 pg/ml. The mean estradiol/estrone ratio ranged between 1 and 2.5 in both groups but fluctuated widely in the patch group. Follicle-stimulating hormone was suppressed in both groups; however, the decrement in the pellet group was greater (p less than 0.002). There was a significant increase in high-density lipoprotein cholesterol and a decrease in total cholesterol/high-density lipoprotein cholesterol at 12 weeks with the pellet but only at 24 weeks with the patch. The urinary calcium/creatinine ratio was reduced more consistently with the pellet than with the patch. Hot flushes were eliminated in all subjects.
Administration, Cutaneous↗
Effects of oral contraceptives on the borderline NIDD patient.
With oral contraceptives (OCs), estrogen and progestogen doses, as well as the type of progestogen used, seem to directly affect glucose tolerance and insulin resistance. Other factors that influence these parameters are a patient's weight and age, family history of diabetes, and previous gestational diabetes. In normal-weight women with previous gestational diabetes, low-dose OCs do not appear to directly affect glucose tolerance, plasma insulin levels, or insulin binding to monocytes. This paper reports the initial data from a study employing low-dose OC formulations in obese patients with a history of either Class A1 or A2 gestational diabetes. Although results are preliminary, they do suggest that Ovcon 35, a low-dose norethindrone-containing OC, may be safe in Class A1 diabetics; in Class A2 diabetics, Ovcon 35 is associated with significantly less change in oral glucose tolerance at 3 months than is the triphasic Triphasil.
Adolescent↗
Termination of early gestation with the anti-progestin steroid RU 486: medium versus low dose.
RU 486 is a synthetic steroid which has antiprogesterone and antiglucocorticoid activity. In order to determine the optimal dosage of this drug to terminate early pregnancy, we treated 106 healthy women with normal pregnancies by real time ultrasound examination whose gestational duration was less than 49 days from onset of last menses with either a medium or low dose treatment regimen. A total of 66 patients received the medium dose regimen (100 mg/day X 7 days). Another 10 patients received ergonovine (0.2 mg/day X 6 doses) on Day 4 of the same RU 486 treatment regimen. In the first group, 48 (73%) aborted successfully and, of the second group, 6 (60%) aborted. Eighty percent of the subjects in this group of 76 patients reported side effects of nausea and vomiting, heavy bleeding, severe menstrual cramps or headache. All these side effects were successfully treated with analgesic and antiemetic medication. The remaining 30 subjects were treated with a low dose regimen (50 mg/day X 7 days). Of these 30, 15 (50%) aborted; this incidence was significantly less (p less than 0.05). Following the medium dose treatment regimen, the AM cortisol levels were significantly elevated on treatment Days 4 and 8, as compared to baseline (p less than 0.001), although the mean levels were still within the normal range. With the low dose, there was a non-significant rise in AM cortisol values. Thus the rise in cortisol was significantly greater in the former group than the latter (p less than 0.05). With the medium dose regimen, the women who aborted had significantly lower (p less than 0.05) pretreatment mean B-HCG and progesterone levels than the group that failed to abort. Mean serum levels of RU 486 were not significantly different between the group who aborted and those who did not. RU 486 is a promising agent for termination of early pregnancy.
Abortion, Induced↗
Pharmacokinetics and metabolism of RU 486.
The effects of dose on the initial pharmacokinetics and metabolism of an antiprogesterone steroid RU 486 (mifepristone) were studied in healthy female volunteers after administration of RU 486 as a single dose of 50-800 mg. The concentrations of RU 486 and its monodemethylated, dimethylated and hydroxylated non-demethylated metabolites were measured specifically after Chromosorb-column chromatography by HPLC. Their relative binding affinities to the human uterine progesterone receptor were also determined. Micromolar concentrations of the parent compound in blood were reached within the first hour after oral administration. The pharmacokinetics of RU 486 followed two distinct patterns in a dose-dependent fashion. With a low dose of 50 mg the pharmacokinetics followed an open two-compartment model with a half-life of over 27 h. With the doses of 100-800 mg the initial redistribution phase of 6-10 h was followed by zero-order kinetics up to 24 h or more. Importantly, after ingestion of doses higher than 100 mg of RU 486 there were no significant differences in plasma concentrations of RU 486 within the first 48 h, with the exception of plasma RU 486 concentrations at 2 h. After single oral administration of 200 mg unchanged RU 486 was found 10 days later in two subjects. The elimination phase half-life with this dose, calculated between day 5 and 6, was 24 h. Micromolar concentrations of monodemethylated, didemethylated and non-demethylated hydroxylated metabolites were measured within 1 h after oral administration of RU 486. In contrast to plasma RU 486 concentrations, circulating plasma concentrations of metabolites increased in a dose-dependent fashion. With higher doses the metabolite concentrations were close to, or even in excess to the parent compound. The relative binding affinities of RU 486, monodemethylated, didemethylated and hydroxylated metabolites (progesterone = 100%) to the human progesterone receptor were 232, 50, 21, and 36, respectively. The existence of a high affinity-limited capacity serum binding protein would explain the long half-life and the observed diverging dose-dependent pharmacokinetics. The extravasation of RU 486 after the saturation of serum binding sites would explain the blunted serum peak concentrations of RU 486 with higher doses. The return of the drug back to circulation thereafter explains the zero-order kinetics. High concentrations of circulating metabolites capable of binding to the progesterone receptor suggest a significant contribution of these steroids in the overall antiprogestational action.
Adult↗