Norgestimate and ethinyl estradiol in the treatment of acne vulgaris: a randomized, placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy of a triphasic, combination oral contraceptive (OC), (norgestimate-ethinyl estradiol), in comparison with placebo in the treatment of moderate acne vulgaris. METHODS: Two hundred fifty women were enrolled in a multicenter, randomized, double-blind, placebo-controlled clinical trial to evaluate the effectiveness of norgestimate-ethinyl estradiol in the treatment of acne vulgaris. Subjects were 15-49 years old and had moderate acne vulgaris. Each month for 6 months, subjects received either 3 consecutive weeks of active OC treatment followed by 1 week of inactive drug, or 4 consecutive weeks of color-matched placebo tablets. Efficacy was assessed by facial acne lesion counts, the investigator's global assessment, and the subject's self-assessment. Hormone levels were also measured. RESULTS: Despite the large placebo effect inherent in an acne trial (due to, for example, careful skin care, frequent office visits, regression to the mean), of the 164 subjects who completed the study without major protocol deviations, the OC group was significantly better than the placebo group for all primary efficacy measures: inflammatory lesions (mean reduction, 51.4% compared to 34.6%; P = .01), total lesions (mean reduction, 46.4% compared to 33.9%; P = .001); investigator's global assessment (83.3% compared to 62.5%; P = .001). Free testosterone decreased significantly and sex hormone-binding globulin increased significantly in the OC group, but remained unchanged in the placebo group. CONCLUSION: A triphasic combination of norgestimate and ethinyl estradiol is an effective treatment for moderate acne vulgaris in women with no known contraindication to OC therapy.

Norethindrone--a review of therapeutic applications.

Norethindrone is utilized for numerous noncontraceptive therapies, especially during the menopause. Through an analysis of the literature we have described the pharmacological profile of norethindrone and the potential therapeutic implications of low-dose therapies, with an emphasis on endometrial pathology, climacteric symptoms, lipid metabolism, and bone density.

A norgestimate-containing oral contraceptive: review of clinical studies.

Despite the well-documented efficacy and safety of low-dose oral contraceptives, the development of newer formulations containing highly selective progestins with minimal or no androgenic activity has been a goal of pharmaceutical research. The efficacy and safety of norgestimate, a progestin with inherently low androgenicity, in combination with ethinyl estradiol, has been examined in several phase II and phase III clinical studies, and these are reviewed. Norgestimate/ethinyl estradiol has proved to be a low-dose oral contraceptive with high selectivity that provides the cycle control of older oral contraceptive formulations with comparable efficacy. Results of comparison studies between norgestimate/ethinyl estradiol and formulations containing norgestrel, a progestin with relatively greater androgenic activity, in combination with ethinyl estradiol, are reported for effects on lipid and lipoprotein levels and carbohydrate metabolism. Norgestimate/ethinyl estradiol consistently produced statistically significant increases in high-density lipoprotein cholesterol and improvement in the ratio of low-density lipoprotein cholesterol to high-density lipoprotein. In contrast, norgestrel/ethinyl estradiol produced statistically significant decreases in high-density lipoprotein cholesterol and potentially adverse changes in the low-density/high-density lipoprotein ratio. Phase II studies have confirmed that norgestimate/ethinyl estradiol has low androgenic activity and causes minimal effect on coagulation factors and carbohydrate metabolism.

PIP: Despite the well-documented efficacy and safety of low-dose oral contraceptives (OCs), the development of newer formulations containing highly selective progestins with minimal or no androgenic activity has been a goal of pharmaceutical research. The efficacy and safety of norgestimate, a progestin with inherently low androgenicity, in combination with ethinyl estradiol (EE), has been examined in several phase II and phase III clinical studies, and these are here reviewed. Norgestimate/EE has proven to be a low-dose OC with high selectivity which provides the cycle control of older OC formulations with comparable efficacy. The results of comparison studies between norgestimate/EE and formulations containing norgestrel, a progestin with relatively greater androgenic activity, in combination with EE, are reported for effects on lipid and lipoprotein levels and carbohydrate metabolism. Norgestimate/EE consistently produced statistically significant increases in high-density lipoprotein (HDL) cholesterol and improvement in the ratio of low-density lipoprotein (LDL) cholesterol to HDL. In contrast, norgestrel/EE produced statistically significant decreases in HDL cholesterol and potentially adverse changes in the LDL/HDL ratio. Phase II studies have confirmed that norgestimate/EE has low androgenic activity and causes minimal effects on coagulation factors and carbohydrate metabolism.

Review of the endometrial effects of estrogens and progestins.

Several controversial areas have been reviewed. It would seem from the evidence at hand that progression from endometrial hyperplasia to endometrial carcinoma does occur in a significant percentage of women and that endometrial hyperplasia, particularly adenomatous hyperplasia and atypical hyperplasia, must be regarded as premalignant changes. Gambrell believes that all stages of hyperplasia should be regarded as premalignant. Previous and retrospective studies provide evidence implicating estrogens in the causation of both endometrial hyperplasia and endometrial carcinoma. Although some of these studies may have design flaws, the amount of data is substantial. Prospective studies have demonstrated an increased risk of hyperplasia in women treated with estrogens. An increased risk of endometrial carcinoma in estrogen users compared with nonusers has been suggested even more recently. Reviewed as a whole, the cumulative evidence provided by these studies clearly supports this association, and it would appear the only issue left to resolve may be the magnitude of the association. Cyclic administration of estrogens may decrease the risk of development of endometrial carcinoma. It would seem, however, that such administration does not totally eliminate risk under any circumstances, and in fact, a dose-related relationship appears to persist. It seems well established that progestogens do decrease the risk of both endometrial hyperplasia and endometrial carcinoma associated with the administration of estrogen to peri- and postmenopausal women. Such reduction in risk is significant and lower relative risks in estrogen/progestogen treated women have been reported compared to untreated women. This reduction in risk has been reported in a variety of studies. Whitehead and co-workers have provided a clear biochemical mechanism for progestogen protection of the endometrium in the antagonism of estrogen at the endometrial cellular level. The evidence at hand in the literature would suggest that progestogens should be administered for at least 10 days per cycle. In summary, there is good evidence that the addition of a progestin to estrogen therapy prescribed for the symptoms of menopause provides protection from endometrial hyperplasia and related carcinoma. The protection conferred is greater than that afforded by cyclical estrogen-alone therapy, and allows for continuous therapy, hereby providing greater symptomatic relief. There is little evidence for adverse effects caused by the added progestins, but further studies of women on combined therapy will undoubtedly be warranted.

Lipid and carbohydrate effects of a new triphasic oral contraceptive containing norgestimate.

Data are reported from the combined results of two studies assessing the lipid and carbohydrate effects of a triphasic preparation of norgestimate and ethinyl estradiol (Ortho TriCyclen, Tri-Cilest) over a 2-year period in 1,783 healthy women. Mean values for serum levels of high-density lipoprotein cholesterol (HDL-C) were increased significantly, with a percent change at 24 months of 13.2. Values for the ratio of low-density lipoprotein cholesterol to HDL-C were reduced throughout the study period (mean change of -6.4% at cycle 24). There were no clinically significant changes in fasting blood glucose levels or insulin levels or in values for glycosylated hemoglobin. These results are consistent with those of previous studies and indicate that the triphasic preparation of norgestimate and etinyl estradiol is a selective and minimally androgenic oral contraceptive agent. Long-term therapeutic benefit may accrue from the favorable influences on the lipid profile.

Comparative review of third-generation progestins.

Desogestrel, gestodene, and norgestimate represent a new generation of progestins designed for use in oral contraceptives. A high degree of efficacy has been retained in these progestins, and the adverse metabolic impact exhibited by older progestins has been reduced considerably. The clinical profile of each progestin, as it is marketed in Europe in combination with ethinyl estradiol, is reviewed. Direct comparisons are made whenever applicable. The major advantages of these formulations over the older combined oral contraceptives are that they have less effect on lipid metabolism and on carbohydrate metabolism, and they are less androgenic. The clinical implications of these findings are discussed.

Cyclic fluctuations in human serum lipid and apolipoprotein levels during the normal menstrual cycle: comparison with changes occurring during oral contraceptive therapy.

The influence of menstrual cycle phases and hormonal contraception on serum lipid and apolipoprotein (apo) levels was investigated in a group of normally menstruating young women. The study period covered a normal menstrual cycle (pretherapy), the fourth cycle of treatment with a triphasic oral contraceptive (OC) preparation, and the cycle immediately following interruption of therapy (cycle 5, posttherapy). Cycle phases were defined on the basis of serum hormone levels and basal body temperature determinations. Significant differences in cholesterol (free and esterified) levels were observed during the menstrual phase of both the normal menstrual cycle (lower) and the OC cycle (higher), when compared with the other phases. Triglycerides, which were higher under OCs, fluctuated similarly throughout the two cycles, but phase differences did not reach statistical significance. Apo AI and apo B were both higher under OCs, and apo B followed a trend similar to cholesterol during the two cycles. During the first month after discontinuation of OCs, cholesterol levels returned progressively to baseline values, while triglycerides were only partially decreased. We conclude that cyclic fluctuations in lipid levels do occur under the influence of both endogenous and exogenous sex hormones.

PIP: Total and free cholesterol, triglycerides, and apolipoproteins apo-A1 and B were determined at precise phases of a pre-therapy menstrual cycle, the 4th cycle on a triphasic oral contraceptive, and in the 1st post-therapy menstrual cycle in 18 women. The triphasic pill contained 5 mcg ethinyl estradiol and 180, 215 and 250 mcg norgestimate for 7 days each (ORF 10131 Triphasic, Ortho Pharmaceuticals, Raritan, NJ). Total cholesterol and triglycerides were measured enzymatically by autoanalyzer (Abbott Bichromatic Analyzer 100), free cholesterol by commercial kit (Boehringer-Mannheim, Mannhein, Germany), and apolipoproteins by electroimmunoassay (Hydragel Apo A1/B, Sebia, Issy- les-Moulineaux, France), with strict quality control using commercial standards. Sera were sampled in 4 phases: Days 3, 4 or 5 of menses, in the follicular phase during rising or peak estradiol levels, at ovulation at peak or highest LH level, and in luteal phase at peak progesterone level. In pill cycles, sera were sampled during each week. Total cholesterol was significantly lower in the menstrual phase, rose on average 9.2% in follicular phase (range -6.8% to +34.4%, in 13 of 18 women), and declined only slightly in luteal phase. Free and esterified cholesterol showed a similar pattern. Triglycerides similarly were lowest in menstrual phase, but were not significantly higher during menstrual cycles. In oral contraceptive cycles, total cholesterol fell an average of 10.7% in the 1st week, and remained at that level until the next pill-free interval or upon discontinuation, when cholesterol rose 11.2%. After discontinuation of the pill, all women resumed normal ovulatory cycles and showed stepwise normalization of cholesterol. Apo-A1 was significantly higher in pill cycles and pill-free intervals than in normal menstrual cycles (p0.001 at all 4 sample points); apo-B was also significantly higher in all samples form pill cycles (p0.05-0.001). There was no correlation between cholesterol levels and any of the hormone levels measured, estradiol, progesterone, LH or FSH.

Endometrial morphology in asymptomatic postmenopausal women.

Few data are available regarding endometrial histologic features in asymptomatic perimenopausal and postmenopausal women. This study encompasses endometrial biopsy specimens obtained from 801 such women before enrollment in a multicenter study of estrogen-progestin replacement. One endometrial cancer was found (0.13%); four additional biopsy specimens showed atypia (total 0.63%). The endometrium was atrophic in 373 (46.9%), proliferative in 133 (16.7%), secretory in 54 (6.8%), and hyperplastic in 41 (5.2%). Insufficient tissue for diagnosis was obtained in 195 (24.5%). We conclude that the yield for neoplasia is so low that screening endometrial biopsy is not justified in asymptomatic perimenopausal and postmenopausal women.

Pharmacologic and pharmacokinetic characteristics of norgestimate and its metabolites.

Biotransformation, pharmacologic, and pharmacokinetic studies of norgestimate and its metabolites indicate that 17-deacetyl norgestimate, along with the parent drug, contributes to the biologic response. The postulated metabolic pathway, which is based on the identification of urinary products had indicated that three metabolites of norgestimate, 17-deacetyl norgestimate, 3-keto norgestimate, and levonorgestrel, might participate in the response. The pharmacologic evaluation of these metabolites demonstrates that only 17-deacetyl norgestimate has a pharmacologic profile consistent with that of norgestimate, and significant concentrations of this metabolite have been measured in the serum of women after the administration of norgestimate. These studies indicate that 17-deacetyl norgestimate contributes to the pharmacologic response to norgestimate.

Prevention of cardiovascular risk in women. A new concern for the obstetrician/gynecologist.

Cardiovascular disease is the leading cause of death in American women, accounting for nearly half a million deaths annually. While most of these women are postmenopausal, data from the Bogalusa Heart Study have shown that fatty streak formation begins early in life, perhaps even in childhood. Successful risk intervention is best initiated early in the process, before the clinical manifestations of disease become apparent. Several major risk factors for cardiovascular disease--elevated cholesterol, elevated blood pressure, and cigarette smoking--are amenable to intervention. The critical role of cholesterol in the pathogenesis of cardiovascular disease, and the impact of even small fluctuations of important subfractions on CV risk have been demonstrated in numerous epidemiologic and clinical studies. A sensitive predictor of cardiovascular risk appears to be the high-density lipoprotein (HDL) cholesterol fraction, which is considered cardioprotective if elevated and a significant independent risk factor if decreased. Reductions in HDL have been documented following the use of even low-dose oral contraceptives containing progestins of high androgenic activity. Elevated LDL cholesterol may be an independent risk factor for CV disease in women. Hence, changes in the LDL/HDL ratio may be more sensitive predictors of change in CV risk. Major risk factors for CV disease in women are outlined with specific reference to the effects of oral contraceptives on lipoproteins.

Influence of a triphasic oral contraceptive preparation on plasma lipids and lipoproteins.

The influence of a triphasic oral contraceptive preparation on plasma lipid, lipoprotein, and apolipoprotein levels was studied in 20 women during 12 treatment cycles. Multiple blood samples representing all phases of the therapeutic cycle as well as posttherapy were obtained. Total and low-density lipoprotein (LDL) cholesterol fluctuated transiently in the earlier part of the study but after 9 and 12 cycles of therapy did not differ from baseline. Cyclic elevations in total cholesterol corresponding to changes in LDL cholesterol were noted twice. Total high-density lipoprotein (HDL) cholesterol remained remarkably stable over the entire study while HDL2 cholesterol decreased and HDL3 cholesterol increased. Triglycerides (total and lipoprotein fractions) increased during treatment and fell to baseline levels within one posttreatment cycle. Very low-density lipoprotein (VLDL) cholesterol was also elevated during the study. Apolipoprotein (apo) AI, apo AII, and apo B rose under therapy, the latter increase producing a lowered LDL cholesterol/apo B ratio. Apolipoprotein E showed a temporary decrease early in the study but otherwise remained unchanged.

Cluster of abortion deaths at a single facility.

This report describes a cluster of four abortion-related deaths at a single facility from 1979 to 1983. The deaths followed curettage abortions at eight to 18 weeks' gestation. One death was attributed to a prolapsed mitral valve, and one was attributed to spontaneous ventricular fibrillation. Two deaths, which occurred within three weeks of each other, were caused by hemorrhage from uterine perforation. The person who allegedly performed the last two abortions was not licensed to practice medicine, nor was he under the supervision of a licensed physician. The estimated death-to-case rate at this facility (57 per 100,000 abortions) is significantly higher than the national rate (1.2 per 100,000 abortions, P less than .001). To prevent such situations, prompt treatment of abortion complications and community-based surveillance of serious morbidity should be performed.

Causes of maternal mortality in the United States.

Among 2475 maternal deaths that occurred in the United States from 1974 to 1978, 408 were related to pregnancies with abortive outcomes, and 2067 were related to other causes. Ectopic pregnancy was the most frequent cause of death in the former group. Embolism, hypertensive disease of pregnancy, obstetric hemorrhage, and obstetric infection were the most common causes of death in the latter group. Women who were 30 years of age or older or of minority race were at increased risk of death. Nationwide surveillance of maternal mortality is feasible and should help to increase the safety of childbearing.

Ectopic pregnancy mortality, United States, 1979 to 1980: clinical aspects.

Ectopic pregnancy has recently become a major cause of maternal mortality in the United States. Despite its increasing public health impact, relatively little is known about the clinical epidemiology of this condition. Therefore, the authors investigated all reported deaths from ectopic pregnancy in the United States occurring in 1979 and 1980, to determine characteristics of, and risk factors for, fatal ectopic pregnancy. Most women (85%) died from hemorrhage. Abdominal and interstitial implantations were more likely to become symptomatic later in gestation and to be fatal than were tubal implantations. Of those deaths for which circumstances were known, more prompt diagnosis and treatment of ectopic pregnancy by health professionals might have prevented one-half of the deaths. One-third of the deaths might have been prevented if the women had notified or visited a physician more promptly after the onset of symptoms. Timelier action by women and health professionals could reduce ectopic pregnancy mortality.

Epidemic of gynecomastia among illegal Haitian entrants.

Gynecomastia may occur as a normal physiologic development at certain ages or as a result of a variety of pathological conditions. An outbreak of gynecomastia was investigated at two processing centers of the Immigration and Naturalization Service (INS) between December 2, 1981, and May 14, 1982. At the Fort Allen Service Processing Center, Puerto Rico, gynecomastia was initially detected in 77 of 540 Haitian male entrants (14 percent) and in only 6 of 186 male employees of the center (3 percent) who were 18-50 years old; the difference in prevalence was statistically significant. At the Krome North Service Processing Center in Miami, Fla., gynecomastia was initially detected in 52 of 512 Haitian males 18-50 years old (10 percent). Two case-control studies did not demonstrate an association between gynecomastia and a number of factors that might have been related to an exogenous estrogen or to a substance with an estrogenic effect. Estrogen or estrogen-like substances were not found in food, water, or environmental samples. When the populations were rescreened several months later, 76 of the persons with gynecomastia detected in the first screening had had total or partial remission. Persons with remission had arrived earlier--a mean of 21.6 days for those at Fort Allen and 36.7 for those at Krome--than did those with newly detected gynecomastia and those with continuing cases. The difference in arrival dates was significant (P less than .005 for Fort Allen and P less than .001 for Krome). These results, in view of nutritional deprivation in Haiti, suggest that these cases may have been an outbreak of refeeding gynecomastia.

Midtrimester abortion. Intra-amniotic instillation of hyperosmolar urea and prostaglandin F2 alpha v dilatation and evacuation.

Although dilatation and evacuation (D&E) is currently the most common method of midtrimester abortion in the United States, the intra-amniotic instillation of hyperosmolar urea and prostaglandin F2 alpha combined (U-P) has been proposed as a safer technique. To evaluate the comparative safety of U-P and D&E, we analyzed 2,805 U-P and 9,572 D&E abortions at 13 to 24 menstrual weeks' gestation. The U-P procedure resulted in significantly more serious complications than D&E (1.03 v 0.49 per 100 abortions). After adjusting for patient age, race, parity, follow-up information, and preexisting conditions, the relative risk of serious complications associated with U-P was 1.9 (95% confidence interval, 1.2 to 3.1). This advantage for D&E stems from its applicability to the 13- to 16-week interval. Although D&E appears to be safer overall in the midtrimester, for women obtaining abortion after 16 weeks, the rates of serious complications were comparable, with a relative risk of 1.0 (95% confidence interval, 0.4 to 2.5).

Fatal hemorrhage from legal abortion in the United States.

Deaths from hemorrhage associated with legal induced abortion should not occur. Yet hemorrhage was the third most frequent cause of death from legal abortion in the United States between 1972 and 1979. This study was undertaken to document the scope of the problem, to identify risk factors for fatal hemorrhage and to recommend ways of preventing these deaths. Deaths were identified through the CDC's nationwide surveillance of deaths from abortions; information on numbers and characteristics of women having legal abortions was obtained from CDC and the Alan Guttmacher Institute. Twenty-four women died from hemorrhage after legal abortion in the United States from 1972 to 1979, for a death-to-case rate of 0.3 deaths per 100,000 abortions (95 per cent confidence interval 0.2 to 0.5). Women who died from hemorrhage were significantly older than those who died from other causes (27.6 versus 24.4 years; p less than 0.05). Documented uterine perforation or rupture was far more frequent among women who died from hemorrhage than those who died from other causes (71 versus 8 per cent; p less than 0.001). Women who sustained uterine perforation or rupture were over 1,000 times more likely to die from hemorrhage than those who did not. Deaths from hemorrhage can be eliminated by preventing uterine trauma during abortion and by rapidly diagnosing and treating hemorrhage if it occurs.

PIP: All deaths from hemorrhage (excluding disseminated intravascular coagulation) after legal abortion in the US were analyzed and compared with legal abortion deaths from all other causes during the January 1972 to December 31, 1979 period. The cause of death in each instance was determined after review of information from the woman, her family or friends, the medical staff; clinic or hospital records; autopsy reports; and death certificates. 24 women died from hemorrhage after legal abortion in the US from 1972-79. During this interval, 7,298,000 legal abortions were reported to the Centers for Disease Control (CDC). The death to case rate for hemorrhage from legal abortion during this period was 0.3 deaths/100,000 abortions. During this same interval, 132 women died of other causes related to legal abortion. No consistent temporal trend in deaths from hemorrhage after legal abortion was evident. The death to case rate for hemorrhage by year ranged from 0.1-0.5 deaths/100,000 abortions, reflecting the small numbers of such deaths each year. The proportion of all legal abortion deaths that was attributable to hemorrhage varied widely year by year, ranging from 4-36%. Women who died from hemorrhage after legal abortion were significantly older than women who died from other causes. Uterine perforation or rupture was far more frequent among women who died from hemorrhage than from other causes (71 versus 8%). Those who died from hemorrhage were 9.4 times more likely to have sustained trauma to the uterus than those who died from other causes. Few other important differences emerged between the 2 groups. Calculation of characteristic specific death to case rates revealed several factors associated with an increased risk of death from hemorrhage. Age was a powerful risk factor for fatal hemorrhage, the risk increasing with advancing age. Hemorrhage requiring transfusion was significantly more frequent among older women. Women of minority races had a higher risk of death from hemorrhage, although this was true for other causes of death as well. Gestational age also influenced the risk of death from hemorrhage. The risk increased progressively through the 16-20 week interval, after which it declined. Overall, the risk of death from hemorrhage was higher in hospitals. Preexisting medical condtions and incomplete abortion increased the risk of death from abortion. Women who sustained uterine perforation or rupture had a risk of death from hemorrhage over 1000 times that of women without this trauma. Uterine trauma caused the bleeding in 17 of the 24 fatal instances of hemorrhage. Lack of adequate postoperative monitoring or treatment of hemorrhagic shock was common to all 24 deaths.

Coagulopathy and induced abortion methods: rates and relative risks.

PIP: The relative risks of coagulopathy from suction curettage, dilatation and evacuation (D and E), and saline instillation were examined using the records of all women obtaining abortions at the Inglewood Hospital in California from February 1980-September 1981. Abortion-related coagulopathy cases were defined as those having both clinical evidence of nonclotting hemorrhage and laboratory confirmation of lower than expected fibrinogen levels (200 mg/dl). During the study period, 13,272 abortions were done by suction curettage, 2619 by D and E, and 304 by saline instillation. 8 cases of coagulopathy were identified. 1 case was associated with suction curettage, 2 with saline instillation, and 5 with D and E. The rates for coagulopathy/100,000 procedures were 8 for suction curettage, 191 for D and E, and 658 for saline instillation. Compared with that of suction curettage, the relative risk of coagulopathy associated with D and E was 25 and of saline instillation, 87, both statistically significant. The relative risk associated with saline instillation versus D and E was 3.4, not statistically significant. The study presents the experience of a single institution with a single group of similarly trained physicians, and uses uniform diagnostic criteria for coagulopathy, but the findings were based on the experience of a limited patient population and the demographic characteristics of the 16,195 women were unavailable, so that potential confounders such as age and parity could not be controlled. Large series are required to define more precisely the risk of coagulopathy for the various abortion methods.^ieng