Objective: To investigate the clinical efficacy of mild inhibition of ovarian steroidogenesis by very low-dose ketoconazole during induction of ovulation in patients with polycystic ovary syndrome (PCOS).Design: Prospective, randomized, cross-controlled study in consecutive cycles.Setting: Large tertiary care center.Patient(s): Eighteen patients with PCOS undergoing hMG superovulation with or without ketoconazole.Intervention(s): A fixed hMG dosage was initiated on cycle days 5-9 in both of the study cycles. Further hMG adjustment was done according to serum E-2 levels and follicular measurements. Ketoconazole was administered in one of the cycles by two protocols.Main Outcome Measure(s): Serum E-2 and P levels, lead follicles, pregnancy rate, and development of ovarian hyperstimulation syndrome.Result(s): Although higher daily hMG doses were needed in cycles with ketoconazole compared with cycles without the drug, the peak E-2 levels were substantially lower in the ketoconazole cycles. Although the number of lead follicles did not differ between treatments, the addition of ketoconazole significantly reduced the number of hyperstimulated cycles. Consequently, the cancellation rate dropped dramatically, thus yielding a higher pregnancy rate per patient in the ketoconazole protocols.Conclusion(s): Use of a very low dose of ketoconazole during ovulation induction effectively attenuates ovarian steroidogenesis in patients with PCOS. This effect may serve as an adjunct to better control the ovarian response in women who are prone to hyperstimulated cycles. (Fertil Steril(R) 1999;72:26-31. (C)1999 by American Society for Reproductive Medicine.).

OBJECTIVE:Ovarian hyperstimulation is associated with a significant increase in ovarian steroid hormone production. Since such high levels of sex steroids may influence the activity of other endocrine glands, as well as affecting lipid metabolism, we studied the effect of ovarian hyperstimulation on the hormonal and lipid profile.STUDY DESIGN:In ten patients who were treated with human menopausal gonadotropins (hMG) for in vitro fertilization (IVF), the serum levels of dehydroepiandrosterone (DHEA), 17-hydroxyprogesterone, insulin, cortisol, growth hormone, thyroid-stimulating hormone, and prolactin, as well as total cholesterol, low-density-lipoprotein cholesterol (LDL-C), high-density-lipoprotein cholesterol (HDL-C), triglycerides, and free fatty acids were monitored. These were correlated with estradiol and free and total testosterone levels.RESULTS:Increased estradiol and free testosterone levels were associated with an increase in DHEA concentration. A correlation was found between increased estrogen level and decreased total cholesterol, triglyceride, and LDL-C levels; HDL-C levels remained unchanged. There was a positive correlation between the estradiol levels and free fatty acid elevation.CONCLUSION:Ovarian hyperstimulation induced changes in lipoprotein lipid content. However, the treated women faced no increase in cardiovascular risk, since their lipoprotein lipid levels were not affected.

Objective: To investigate the effects of a low-dose ketoconazole on ovarian steroidogenesis and on serum androgen levels in polycystic ovary syndrome (PCOS).Design: In vitro, human granulosa-luteal cells were incubated with ketoconazole and radiolabeled steroid substrates, to follow their metabolic fate by thin-layer chromatography analysis. In vivo, normally cycling women (n = 7) in their luteal phase were administered one tablet of 200 mg ketoconazole at 8 A.M. Serum steroid levels, sampled basally and at 12 P.M., 4 P.M., and 8 A.M. the next morning, were compared with untreated control group (n = 7) values. Polycystic ovary syndrome women (n = 11) were similarly administered ketoconazole 6 to 10 days after occurence of spontaneous menses. Adrenal origin of hyperandrogenemia was excluded by stimulation with ACTH and a normal basal DHEAS. The steroid diurnal variation was determined in the same patients a day before treatment.Results: In vitro, ketoconazole selectively inhibited the key steroidogenic cytochromes, namely P450(scc), P450(17 alpha), and P450(arom) (IC50 = 0.5 to 1.0 mu g/mL). In vivo, in the luteal phase, ketoconazole transiently decreased serum values (mean +/- SE) of E(2) (19.2% +/- 2.1%) and P (38.3% +/- 8.5%) within 4 to 8 hours. The same low-dose ketoconazole, administered to PCOS women, decreased serum values of androstenedione (17.6% +/- 4.7%), T (24.6% +/- 7.6%), and free T (30.7% +/- 7.7%). In contrast, 17 alpha-hydroxyprogesterone increased concomitantly (78.5% +/- 10.8%), suggesting a greater suppressibility of the P450(17 alpha) lyase activity. The E(2) levels in PCOS patients were slightly elevated (29.1% +/- 5.6%), resulting in a 1.7- to 2.3-fold increase of the E(2):T ratio.Conclusions: These findings suggest that a low-dose ketoconazole may facilitate a decreased intraovarian T:E(2) ratio, which may prove favorable for follicular maturation in PCOS.

A serological test for chlamydial infection was administered to 281 Jerusalem women in order to determine the rate and influence of Chlamydia on pregnancy outcome. Serological indication of active infection was present in 7.8% of the tested women, while 15.3% were shown to be positive for Chlamydia. Among the ultraorthodox subpopulation of Mea Shearim, serological indication of active infection was present among 5.9% of the women, and 12.3% of this population tested positive. In comparison, women from the secular subpopulation had 12.7% serological indication of active infection and 22.95% tested positive (P <0.01). There were no statistically significant differences between pregnancy duration, birthweight, incidence of premature uterine contractions, premature rupture of membranes, and postpartum febrile morbidity in the infected and noninfected groups. Women with a previous history of induced abortions showed a significantly higher evidence of past Chlamydia infection (9.3%) when compared with the women who did not have an infection (1.4%) (P <0.006). Among the ultraorthodox women with positive or active infection, 41% had suffered at least one spontaneous abortion, as compared with 25% of the religious women who had no serological evidence of infection.

The combination of amenorrhea, galactorrhea, and hyperprolactinemia in a young woman usually suggests a prolactin-secreting adenoma of the anterior pituitary gland. Primary thyroid failure may also be associated with hyperprolactinemia, galactorrhea and suprasellar enlargement of the pituitary. 2 women, aged 23 and 28, respectively, presented with the latter syndrome. 1 was even a candidate for neurosurgery. However, because serum TSH and prolactin levels were elevated, thyroxin replacement therapy was started. It induced normal menses, galactorrhea stopped, and in follow-up CT scans the pituitary become normal in size. Hyperprolactinemia with secondary hypothyroidism, caused by a pituitary adenoma, must be distinguished from primary hypothyroidism, also a cause of hyperprolactinemia.

Ketoconazole (KCZ), a widely used antifungal drug, has been reported in humans to inhibit adrenal and testicular steroidogenesis by interfering with the cytochrome P-450-dependent enzymes. The purpose of this study was to investigate the drug effect on steroidogenic human granulosa-luteal cells, obtained by follicular aspiration from mature follicles of gonadotropin-treated women. Cells were cultured in long-term monolayers, and the steroid production was assayed by radioimmunoassay. A profound inhibition of ovarian cell secretion of progesterone (P), testosterone (T) and estradiol was found. At a low concentration (5 micrograms/ml), KCZ failed to inhibit the conversion of pregnenolone to P, mediated by the non-cytochrome 3 beta-hydroxysteroid dehydrogenase-isomerase enzyme (3 beta-HSDH). At a similar concentration, P secretion by human chorionic gonadotropin (hCG; 100 mIU/ml) -treated cells was decreased by 68% (P less than 0.001) and therefore, an inhibitory effect of KCZ on the cholesterol side-chain cleavage enzyme (P-450SCC) was assumed. A similar marked inhibitory effect (81%) (P less than 0.001) on T secretion was observed for hCG-stimulated cells given pregnenolone as substrate. The P-450 aromatase was profoundly inhibited (86%) (P less than 0.001) in a reversible manner, by a similar concentration (5 micrograms/ml) of KCZ. These findings suggest that KCZ has the capability to suppress human ovarian steroidogenesis similarly as in testis and adrenal.

Eleven patients presenting with thoracic aortic dissection were studied by computed tomography (CT). CT was usually performed with knowledge of the angiographic diagnosis. In eight cases, CT was definitive. This group included all six patients who received intravenous contrast material by bolus infusion. An algorithmic approach to patients with possible aortic dissection is suggested.

The amplitude and intensity of heart sounds were measured at the chest wall in 25 patients with acute myocardial infarction in order to determine what meaningful clinical information can be derived from observing the intensity of the heart sounds. During the early period after infarction, the first heart sound (S1), the aortic component of the second heart sound (A2), and the pulmonary component of the second heart sound (P2) each were lower (P < 0.001) than the respective heart sounds of 23 normal subjects. Measurable reductions of sounds frequently occurred in the absence of a third heart sound or rales. Prolongation of the ratio of the preejection period over the left ventricular ejection time (PEP/LVET) (P < 0.001) and a reduced rate of isovolumic relaxation (P < 0.001) accompanied the reduced heart sounds. During the course of recovery, the average intensity of A2 increased in 19 of 25 patients. Among the 19 patients who showed an increase in A2, the PEP/LVET decreased (improved) (P < 0.02), and the rate of isovolumic relaxation increased (P < 0.001). Blood pressure did not change. The diminished A2, as shown by recently described mechanisms of production of the second heart sound, is due to a reduction of left ventricular isovolumic relaxation. Similarly, the reduced P2 implies that right ventricular isovolumic relaxation also was affected by the infarction. Variations of S1 seem to relate to variations of the left ventricular contractile state. The results of this study indicate that the intensity of heart sounds at the chest wall in patients with normal valves and normal transmission of sound is measurably diminished in patients following myocardial infarction. Noticeable ausculatory variations of the intensity of heart sounds can serve as a meaningful guide to the evaluation of ventricular performance at the bedside. The amplitude and intensity of heart sounds were measured at the chest wall in 25 patients with acute myocardial infarction in order to determine what meaningful clinical information can be derived from observing the intensity of the heart sounds. During the early period after infarction, the first heart sound (S1), the aortic component of the second heart sound (A2), and the pulmonary component of the second heart sound (P2) each were lower (P < 0.001) than the respective heart sounds of 23 normal subjects. Measurable reductions of sounds frequently occurred in the absence of a third heart sound or rales. Prolongation of the ratio of the preejection period over the left ventricular ejection time (PEP/LVET) (P < 0.001) and a reduced rate of isovolumic relaxation (P < 0.001) accompanied the reduced heart sounds. During the course of recovery, the average intensity of A2 increased in 19 of 25 patients. Among the 19 patients who showed an increase in A2, the PEP/LVET decreased (improved) (P < 0.02), and the rate of isovolumic relaxation increased (P < 0.001). Blood pressure did not change. The diminished A2, as shown by recently described mechanisms of production of the second heart sound, is due to a reduction of left ventricular isovolumic relaxation. Similarly, the reduced P2 implies that right ventricular isovolumic relaxation also was affected by the infarction. Variations of S1 seem to relate to variations of the left ventricular contractile state. The results of this study indicate that the intensity of heart sounds at the chest wall in patients with normal valves and normal transmission of sound is measurably diminished in patients following myocardial infarction. Noticeable ausculatory variations of the intensity of heart sounds can serve as a meaningful guide to the evaluation of ventricular performance at the bedside.

Until development of coronary angiography, angina pectoris was regarded almost exclusively as the result of atherosclerosis of the large coronary arteries. This supposition is no longer tenable. Chest pain indistinguishable from classical angina pectoris has been described in patients having normal coronary vessels. 1-3 Further, typical angina was described in a woman who, during attacks of chest pain, had monophasic current of injury with accompanying life-threatening arrhythmia, yet had normal coronary angiograms. 4 Acute myocardial infarction was verified in two young men in whom subsequent arteriography showed normal coronary vasculature. 5,6 Ischemic signs and symptoms with normal coronary angiograms have been ascribed to deranged oxyhemoglobin dissociation, 7 as well as to small-vessel disease. 2,8 The purpose of this case report is to add thrombocythemia to this dossier. Patient Summary A 40-year-old white woman, the mother of two, was referred for evaluation of disabling chest pain of recent onset. She had

Serum digoxin levels (SDL) were compared with tolerance for the rapidly acting cardiac aglycone, acetyl strophanthidin (AS). AS titration tests were performed on 133 patients with diverse cardiac disorders. All were receiving maintenance digoxin. Both exquisite AS sensitivity and tolerance for a 1.0 mg AS were associated with a wide range of SDL values. Concordance and discordance between the two methods in assessing degree of digitalization were evaluated by considering SDL of 1.4 ng/ml to be the mean value for patients without glycoside-induced cardiac arrhythmia. An SDL of < 1.5 ng/ml with tolerance for 1.0 mg AS and an SDL of > 1.4 ng/ml with sensitivity to 1.0 mg AS or less constituted concordant responses. An SDL of < 1.5 ng/ml with intolerance for 1.0 mg or less AS and an SDL of > 1.4 ng/ml with tolerance for 1.0 mg AS comprised discordant responses. In 60 of 144 (42%) AS titrations discordant results were observed. Severe pulmonic, coronary, and aortic valvular heart disease, as well as old age, contributed to unusual AS sensitivity. Titration with AS clarified pharmacologic quantification of SDL by providing insight into optimum therapeutic glycoside dose.

Tolerance for digitalis during acute myocardial infarction was evaluated by acetyl strophanthidin testing. Fifty-four patients hospitalized in a coronary care unit were studied within 48 hours of admission; continuous electrocardiographic monitoring and the rapid onset in activity of acetyl strophanthidin allowed a precise titration of druginduced arrhythmias. The dose schedule was 0.1 to 0.2 mg every 5 to 6 minutes. Tolerance for 1.0 mg of acetyl strophanthidin or the emergence of gastrointestinal symptoms or electrocardiographic signs of early digitalis intoxication with 1.0 mg or less constituted the test procedure. Forty-eight of the patients (89 percent) tolerated a full dose of acetyl strophanthidin; ventricular ectopic mechanisms developed in only 3 patients (6.0 percent of those receiving 1.0 mg). An increase in blood pressure followed administration of acetyl strophanthidin in 32 (59.3 percent) of the 54 patients. These data suggest that the large majority of patients with acute myocardial infarction and heart failure can safely be treated with digitalis drugs.

Relationships between serum digoxin concentration (SDC) and drug-induced changes in cardiac automaticity were examined in dogs given single and multiple doses of this cardiac glycoside. Dominant serum half-time, measured by radioimmunoassay, was found to be 26.9 hours and rate of decline in SDC was not influenced by pre-existing body digoxin stores within the range studied. Changes in automaticity were assessed by 1) electrical provocation of repetitive ventricular responses (RVR) and 2) tolerance for acetyl strophanthidin (AS) infusion. RVR was demonstrable prior to the appearance of ventricular tachycardia (VT) provoked by digoxin. Post-VT RVR was observed when overt toxicity subsided. Initially, this post-VT RVR was manifest over a wide zone in electrical diastole. Reduction in the cardiac activity of digoxin was measurable from a narrowing in the post-VT RVR zone. Dissipation of digoxin action was also correlated with diminishing SDC; upon disappearance of VT, SDC was 12.7 ± 1.9 ng/ml (S.E.M.) and upon disappearance of 1) post-VT, RVR 7.65 ± 1.0 ng/ml. The effects of digoxin and AS upon cardiac automaticity were additive, and each drug comprised a fraction of the toxic (VT) digitalis dose. Over a range of SDC from 0 to 14 ng/ml, SDC was inversely correlated with AS tolerance. For each 1.0 ng/ml increase in SDC, a mean value of 5.2 µg/kg ± 0.65 less AS was needed to evoke VT.

Meeting Abstracts1 May 1971Correlation of Serum Digoxin Level with Acetylstrophanthidin Tolerance.I. Barr, M.D., M. D. Klein, M.D., B. Lown, M.D., T. Smith, M.D., F. Hagemeijer, M.D.I. Barr, M.D., M. D. Klein, M.D., B. Lown, M.D., T. Smith, M.D., F. Hagemeijer, M.D.Author, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-74-5-817_1 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptWith the advent of a reliable radioimmunoassay it has become possible to quantify serum digoxin levels. Whereas a high serum digoxin level helps confirm toxicity, some overlap with therapeutic glycoside levels exists. In the presence of a normal digoxin level proximity to a toxic state cannot be defined with precision. Degree of digitalization was therefore assessed by both serum digoxin levels and an independent pharmacoassay using acetylstrophanthidin. In 10 anesthetized dogs given 0.04 to 0.08 mg/kg body weight digoxin intravenously 6 hr earlier, the serum digoxin level inversely correlated with the amount of acetylstrophanthidin required to produce ventricular tachycardia (r... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAuthors: I. Barr, M.D.; M. D. Klein, M.D.; B. Lown, M.D.; T. Smith, M.D.; F. Hagemeijer, M.D.Affiliations: Boston, Mass. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byGlykosideDigitalis toxicity: Epidemiology and clinical use of serum concentration measurementsDigitalisChanges in Left Ventricular Performance from Early after Acute Myocardial Infarction to the Convalescent PhaseContribution of Quantitative Assay Technics to the Understanding of the Clinical Pharmacology of DigitalisAssays of digitalis in the blood 1 May 1971Volume 74, Issue 5Page: 817-817KeywordsBody weightGlycosidesRadioimmunoassaysToxicityVentricular tachycardia ePublished: 1 December 2008 Issue Published: 1 May 1971 PDF downloadLoading ...

Fourteen animals of five mammalian species (monkeys, dogs, rabbits, cats, and goats) were digitalized with acetyl strophanthidin and ouabain to an end-point of ventricular tachycardia. RVR was present in all animals before onset and after recovery from digitalis-induced intoxication. The appearance and development of RVR was analogous in all animals studied.