K. Grunwald

The efficacy and tolerability of norgestimate/ethinyl estradiol (250 μg of norgestimate/35 μg of ethinyl estradiol): Results of an open, multicenter study of 59,701 women

The efficacy and tolerability of a new oral contraceptive, norgestimate/ethinyl estradiol (250 μg of norgestimate/35 μg of ethinyl estradiol; Cilag GmbH Research, Sulzbach, Germany) were examined in an open-label study of 59,701 women who were evaluated during 342,348 menstrual cycles; 42,022 women completed the planned treatment regimen of six cycles. A use-efficacy (overall) Pearl index of 0.25 pregnancies per 100 woman-years was calculated based on 342,348 cycles. Tolerability was assessed for all women who completed six treatment cycles. Reductions in mean cycle length and duration of bleeding were noted; 32% of the women experienced reductions in the intensity of bleeding by the end of cycle 6. After six cycles of use, amenorrhea occurred in 1%, spotting in 4%, and breakthrough bleeding in 3% of the participating women. Treatment with norgestimate/ethinyl estradiol had minimal effects on weight, blood pressure, pulse, lipid metabolism, and blood glucose. Adverse effects (acne, nausea, or headaches) occurred at low frequencies and in many cases, were reduced compared with pretreatment levels. The results of this large-scale open trial were comparable with results from two other multicenter trials of the same formulation.

Lipid metabolism in norplant-2 users — a two-year follow-up study

Changes in lipid metabolism in 25 healthy female volunteers during a 24-month application of Norplant-2 were evaluated in an open clinical trial. Total serum cholesterol decreased significantly (p less than 0.05/p less than 0.05) by 10%/9% after 12 months and by 3%/7% (n.s./n.s.) after 24 months of Norplant-2 use (all subjects/subjects completing 24 cycles). Serum triglycerides decreased by 34%/28% (n.s./p less than 0.05) after 12 months and by 29%/25% (p less than 0.05/p less than 0.05) after 24 months of Norplant-2 use (all subjects/subjects completing 24 cycles). HDL-cholesterol decreased significantly by 18%/12% (p less than 0.01/p less than 0.05) after 12 months and by 12%/12% (p less than 0.05/p less than 0.05) after 24 months of Norplant-2 use (all subjects/subjects completing 24 cycles). No statistically significant difference between serum levels of LDL-cholesterol prior to and after 12 and 24 months of Norplant-2 use could be found. VLDL-cholesterol levels decreased significantly by 38%/38% (p less than 0.05) after 12 and by 25%/25% after 24 months of Norplant-2 application (p less than 0.01) (all subjects/subjects completing 24 cycles). Apolipoprotein Al decreased significantly by 23%/23% (p less than 0.001/p less than 0.01) after 12 and by 21%/22% after 24 months of Norplant-2 application (p less than 0.01/p less than 0.01) (all subjects/subjects completing 24 cycles). No statistically significant difference between apolipoprotein All levels prior to and after 12 and 24 months of Norplant-2 implantation could be found. Apolipoprotein B decreased significantly by 27%/17% (p less than 0.05/p less than 0.05) after 12 months of Norplant-2 application (all subjects/subjects completing 24 cycles). The decline after 24 months of Norplant-2 use was not significant. Changes in lipid metabolism caused by oral hormonal contraceptives differ in the various clinical trials; however, most investigators found that serum levels of total cholesterol and triglycerides increase under the application of OCs. Contrary to this, a decrease of total cholesterol and triglycerides under Norplant-2 use was noted. Furthermore, we found a significant decrease of lipoproteins and apolipoproteins--with the exception of LDL-cholesterol and apolipoprotein All, which did not show any significant modifications. Thus, Norplant-2 seems to be non-contributory to cardiovascular risk and might even provide protection against such risks.

Normal values for a short-time ACTH intravenous and intramuscular stimulation test in women in the reproductive age.

Normal values in endocrine testing are the most important precondition for the recognition of disorders of the endocrine system. To establish a reference range for adrenocorticotropic hormone (ACTH) stimulation tests, an intravenous and intramuscular ACTH stimulation test was conducted in 29 female volunteers without hyperandrogenism. A total of 25 IU of ACTH were administered intravenously or intramuscularly and blood sampling was performed before, 1 h and 2 h after ACTH injection. The test was performed on days 3-5 of the menstrual cycle. The following steroid hormones were assessed in the serum: 17 alpha-hydroxyprogesterone, 17 alpha-hydroxypregnenolone, dehydroepiandrosterone, testosterone, free testosterone and 5 alpha-dihydrotestosterone. The normal range was defined by the interval between the 5th and 95th percentiles; additionally the 1st, 25th, 50th, 75th and 99th percentiles are reported. A significant increase of serum hormone levels after ACTH administration could be observed for the following hormones: cortisol, 17 alpha-hydroxyprogesterone, 17 alpha-hydroxypregnenolone and dehydroepiandrosterone. There was no rise after ACTH application for testosterone, 5 alpha-dihydrotestosterone and free testosterone. It could be shown for all hormones that there was no significant difference between the serum levels that were reached after intravenous and intramuscular ACTH injection. Neither could we find a significant difference in the relative increase of the serum hormones when stimulation values were related to basal values. Since in most studies with ACTH stimulation tests, only the serum values 1 h after ACTH application are measured, we investigated whether the measurement of steroid hormones 2 h after ACTH application gave further information. We could demonstrate that for most measured serum hormones the majority of the volunteers had the maximal response 2 h after ACTH application, no matter whether ACTH was injected intramuscularly or intravenously. As a conclusion, we recommend the measurement of the respective hormones not only 1 h but also 2 h after ACTH stimulation. Since there is no increase after ACTH stimulation for total testosterone, free testosterone and 5 alpha-dihydrotestosterone, it is sufficient to assess the basal values of these hormones. Excessive adrenal response is reflected by dehydroepiandrosterone, 17 alpha-hydroxyprogesterone, 17 alpha-hydroxypregnenolone and cortisol.

Treatment of hyperandrogenism in women

In this review the medical therapy of hyperandrogenism is evaluated both by a literature review and by our own experiences at a large outpatient clinic for patients with symptoms of hyperandrogenism. The clinic was established over 15 years ago at the Department of Gynecological Endocrinology and Reproductive Medicine of the University Womens Hospital in Heidelberg, Germany.In addition to the dermatological aspect, therapy using antiandrogens also contributes to avoiding the development of polycystic ovary syndrome, reducing the increased risk of endometrial cancer in cases of hyperandrogenemia and avoiding the associated cardiovascular complications of hyperandrogenemia. About 25—40% of all women aged between 15 and 25 years suffer from acne vulgaris of differing degrees of severity. Since severe psychological strains caused by this may be expected, especially in young women without adequate therapy, systemic antiandrogen treatment is of particular importance.The requirement for available and safe subst...

Oral Contraceptives and Lipid Metabolism

The most important causes of higher mortality in users of oral contraceptives (OC) due to cardiovascular diseases such as thromboembolic insults, myocardial infarction and cerebral insults are related to changes in metabolism: changes in lipid metabolism with development of atherosclerosis, changes in carbohydrate metabolism with development of a chemical diabetes mellitus, and deterioration of the renin-angiotensin-aldosterone system leading to hypertension, changes in blood coagulation, fibrinolysis and morphological changes of blood vessels. These changes are caused predominantly by environmental factors (e. g., nutrition, physical activity, and standard of living) and less by genetic factors.

High preovulatory serum luteinizing hormone level is unfavorable to conception

Serum estradiol, progesterone and luteinizing hormone (LH) levels of 16 pregnant and 58 non-pregnant stimulated in vitro fertilization-embryo transfer (IVF-ET) or gamete intrafallopian transfer (GIFT) cycles have been compared with regard to their predictive value for achievement of pregnancy. Serum estradiol and progesterone pattern of the pregnant and non-pregnant group did not show any significant difference. Around the time of ovulation induction by human chorionic gonadotropin (hCG) the serum LH values proved to be higher in the non-pregnant group than in the pregnant one. In spite of having a permissive function, preovulatory serum estradiol and progesterone seem not to have a predictive value with regard to pregnancy. Elevated preovulatory serum LH is detrimental for pregnancy, therefore the measurement of serum LH beyond hCG administration also, and the cancellation of cycles with high serum LH levels shortly before oocyte retrieval is recommended.

Elevated serum inhibin levels and suppressed luteinizing hormone surge in young patients stimulated with gonadotropins

The physiological role of inhibin and its relation to other sex hormones (estradiol, progesterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH)) has been investigated during gonadotropin-stimulated cycles of 38 in vitro fertilization-embryo transfer/gamete intrafallopian transfer (IVF-ET/GIFT) patients. Human menopausal gonadotropin (hMG) was given from day 3 of the cycle until 1 day before ovulation induction with human chorionic gonadotropin (hCG). Blood samples were taken twice daily and hormone measurements performed by radioimmunoassay or enzyme immunoassay. Patients were divided into two groups: Group A comprised patients < 35 years of age (n = 20) and Group B included patients > or = 35 years of age (n = 18). The pregnancy rate was significantly higher in Group A. During the follicular phase, serum inhibin level rose gradually in both groups but the values were higher in Group A (significantly between days -2 and 0). During the early luteal phase serum inhibin concentrations were similar in both groups. Estradiol pattern did not differ in the two groups. Estradiol pattern did not differ in the two groups. Whilst serum estradiol level did not increase significantly after day 0, serum inhibin concentration reached its peak value 1 day later, on day +1. Serum progesterone was higher in Group A between days +1 and +4 (significantly on days +1, +3 and +4). Serum FSH increased slowly in both groups and did not correlate with serum inhibin concentration. Basal LH concentrations were similar between days -6 and -2 in both groups. Around the time of ovulation induction (day -1, 0 and +1) serum LH was lower in Group A (significantly on day 0).(ABSTRACT TRUNCATED AT 250 WORDS)

Intrauterine Devices: Efficacy and Side Effects

Despite early methods described in Egypt in 2000 B.C. for contraception in camels, the first known human application of intrauterine contraceptives in terms of vaginal and uterine pins occurred 100 years ago. In Germany the development of intrauterine devices originated with a device developed by Richter in 1909 consisting of a natural silk ring (Fig. 1). Later Grafenberg (1926) introduced a metal ring consisting of a mixture of brass, bronze, and copper. The development of new IUDs stopped abruptly when multiple pelvic inflammatory diseases and deaths lead to prohibition of this method for contraception. In 1959 intrauterine devices had a renaissance when the original metal ring of the Japanese Ota was replaced by one made out of plastic and the device used by 20000 Japanese women. In 1962 the Grafenberg ring was admitted to the United States market. The second generation of IUDs are the inert plastic Margulis devices and Dalkon Shield. Since 1970, third-generation copper-containing IUDs have been available, and during recent years progesterone-releasing devices have also become available.