Studies on folliculogenesis and in vitro fertilization outcome after the administration of follicle-stimulating hormone at different times during the menstrual cycle

The authors have undertaken a prospective, randomized clinical trial of six treatments to optimize folliculogenesis in patients prior to oocyte collection, in vitro fertilization, and embryo transfer. All treatments involved the administration of the same daily dose of follicle-stimulating hormone (FSH), but at different times during the antecedent and/or current menstrual cycle. There was a significant difference (P less than 0.01, chi-square test) between treatments in the clinical pregnancy rate/patient (19 clinical pregnancies, 67 patients). No advantages were observed for regimens that involved starting treatment during the antecedent cycle. The study was continued with the three treatments that started during the current cycle (24 clinical pregnancies, 58 patients). The most cost-effective regimen was clomiphene citrate, 100 mg/day for days 2 to 6 inclusive; FSH, 150 units/day for days 1 to 4 inclusive; and human menopausal gonadotropin, 150 units/day from day 5 until the day of human chorionic gonadotropin administration.     

Continuous combined conjugated equine estrogen-progestogen therapy: effects of medroxyprogesterone acetate and norethindrone acetate on bleeding patterns and endometrial histologic diagnosis.

OBJECTIVES: This study was designed to assess the incidence of amenorrhea with continuous combined therapy by using two different progestogens and to determine whether early bleeding predicts subsequent bleeding and endometrial response. STUDY DESIGN: Seventy-nine postmenopausal women on sequential estrogen-progestogen treatment were switched to continuous combined estrogen-progestogen therapy comprising conjugated equine estrogens 0.625 mg daily with either norethindrone acetate 0.35 mg twice daily or medroxyprogesterone acetate 2.5 mg twice daily added continuously for 78 weeks. All bleeding was recorded, and endometrial biopsies were performed at 26 and 78 weeks. RESULTS: Only one third of the women who starting the study had amenorrhea by week 78, but 46 (62%) of these women had withdrawn, mainly because of chronic irregular bleeding. Endometrial atrophy was observed in the majority of biopsy specimens. The two progestogens had similar effects. Bleeding patterns were useful predictors of subsequent bleeding, but not of endometrial response. CONCLUSIONS: Persistent irregular bleeding is common with continuous combined estrogen-progestogen therapy. Women with persistent early bleeding should probably revert to sequential treatment. Regular endometrial sampling is advised.     

Correlation in ages at death from familial ovarian cancer among sisters.

The analysis of pedigrees taken from 97 of 1466 women attending a screening clinic for early familial ovarian cancer showed that there was a strong correlation in the ages at death from the disease among sisters (r = 0.68, confidence limits 0.51-0.82, P < 0.001), but not between mothers and daughters. This information can be used to help counsel women who are considering the appropriate time for more intensive screening or prophylactic oophorectomy.     

The optimal dose of oral norethindrone acetate for addition to transdermal estradiol: a multicenter study

The effects of adding one of three doses (0.5, 0.75, or 1.0 mg/d) of norethindrone acetate for 12 days each month to continuous, transdermal estradiol (0.05 mg/d) have been determined in a prospective, randomized, multicenter study. Significant symptomatic and psychological improvements were observed and, with one exception, were not opposed by the added progestogen. Distinct redness at the site of last patch application was reported by 10% of patients and faint erythema by 30%. However, less than 5% of patients discontinued treatment because of skin problems. Breakthrough bleeding occurred infrequently and all three doses of norethindrone acetate induced a regular pattern of bleeding with secretory transformation in the endometrium. There was no hyperplasia or carcinoma.     

William Farr's legacy to the study of inequalities in health

This section looks back to some of the ground-breaking contributions to public health, reproducing them in their original form and adding a commentary on their significance from a modern-day perspective. To complement this month's theme issue of the Bulletin, Margaret Whitehead assesses the importance of William Farr's contribution to the study of social inequalities in health.     

Studies on the measurement and pharmacodynamics of human follicle-stimulating hormone

The levels of immunoreactive follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), cortisol, and estradiol (E2) have been determined in serial samples of peripheral plasma from four subjects during the continuous, subcutaneous administration of Buserelin (Hoechst [UK] Ltd., Hounslow, UK) (250 micrograms/day) and after the intramuscular injection of purified, urinary FSH (Metrodin, Serono Laboratories [UK] Ltd., Welwyn Garden City, UK) (150 IU). During Buserelin administration the geometric mean levels of FSH and LH as measured by immunoradiometric assay were reduced by 87% and 37%, respectively, when compared with the corresponding values for days 1 and 2 of the menstrual cycle. After the intramuscular injection of FSH, peak levels (from 3.4 to 6.2 IU/l) occurred in peripheral plasma between 6 and 18 hours later. The levels were significantly elevated after 72 hours (P less than 0.01, Student's paired t-test). There was no obvious effect of the drugs on the circadian rhythms of plasma PRL or cortisol, and no significant effect on the circulatory levels of LH or E2.     

Pro-apoptotic actions of exisulind and CP461 in SW480 colon tumor cells involve beta-catenin and cyclin D1 down-regulation

Exisulind and its analogues are inhibitors of cyclic GMP phosphodiesterases (PDEs) that have been shown to activate and induce protein kinase G, resulting in the induction of apoptosis in colon cancer cells. These drugs also reduce beta-catenin protein levels and decrease cyclin D1 mRNA levels in SW480 cells. Herein we report on studies pertaining to exisulind regulation of beta-catenin levels and activity in colon tumor cells. Exisulind and its higher-affinity PDE analogues, (Z)-5-fluoro-2-methyl-(4-pyridylidene)-3-(N-benzyl)-indenylacetamide hydrochloride (CP461) and (Z)-1H-indene-3-acetamide, 5-fluoro-2-methyl-N-(phenylmethyl)-1-[(3,4,5-trimethoxyphenyl)methylene] (CP248), reduced beta-catenin, including the nuclear beta-catenin in SW480 cells (EC(50) approximately 200 microM, 1 microM, and <1 microM, respectively). The 50% reduction of beta-catenin was seen in 8-14 hr. There was no change in beta-catenin mRNA. Exisulind-induced beta-catenin reduction was blocked by the proteasomal inhibitor MG132 (Z-leu-Leu-Leu-CHO), indicating that the effect of exisulind involved ubiquitin-proteasomal degradation. A consequence of reduced beta-catenin in SW480 cells was that exisulind, CP461, and CP248 caused a concentration- and time-dependent decrease in cyclin D1 levels (EC(50) approximately 300 microM, 1 microM, and <1 microM, respectively) in 4 hr. The effect was via decreased cyclin D1 mRNA levels. Exisulind-induced degradation of beta-catenin was not blocked by the inhibition of caspase-3 activity and/or apoptosis, and some SW480 cells showed a reduction in beta-catenin levels before the appearance of early apoptosis indicators. Expression of the N-terminal 170 amino acid fragment of beta-catenin reduced the effects of beta-catenin degradation, cyclin D1 reduction, and the apoptosis response to exisulind. These results indicate that exisulind-induced beta-catenin degradation precedes the induction of apoptosis and that the down-regulation of inappropriate beta-catenin-activated genes accounts in part for the pro-apoptotic effects of exisulind and CP461 in colon tumor cells.     

Effect of occlusion on the percutaneous penetration of linoleic acid and glycerol

The effect of occlusion on the in vitro percutaneous absorption of linoleic acid was investigated. A greater skin concentration of linoleic acid from an ethanolic vehicle was observed in non-occluded experiments compared with occluded experiments (P<0.05). Such changes were not observed as consistently when ethanol was replaced with a less volatile organic solvent (cyclomethicone). These observations were attributed to the increase in the concentration gradient due to the unimpeded evaporation of volatile solvents, which provided a greater driving force and enhanced non-occluded delivery in these systems, compared with occluded systems. Conversely, the percutaneous absorption of a polar material (glycerol) from an aqueous solution did not yield any such differences. While more conclusive comparisons between volatile and non-volatile solvents and penetrants would be required to substantiate fully these comparisons, it is apparent that non-occlusion of volatile solvents may enhance percutaneous absorption. The physicochemical properties of the penetrant, for example its natural state at skin temperature (i.e. solid or liquid) may further determine the degree of enhanced percutaneous absorption compared with occluded environments.     

Prevalence and risk factors of work related asthma by industry among United States workers: data from the third national health and nutrition examination survey (1988-94)

Objectives: To estimate the prevalence of work related asthma and work related wheezing in United States workers. To identify high risk industries that could be targeted for future intervention. To determine the population attributable risk of work related asthma and work related wheezing.

Methods: The third national health and nutrition examination survey, 1988–1994 (NHANES III) was analyzed to determine the prevalence of work related asthma and wheezing and to identify initially defined industries at risk among United States workers aged 20 and older. Separate logistic models were developed with work related asthma and work related wheezing as outcomes. Work related asthma was defined as affirmative response to questions on self reported physician diagnosed asthma and work related symptoms of rhinitis, conjunctivitis, and asthma. Work related wheezing was defined as affirmative response to questions on self reported wheezing or whistling in the chest in the previous 12 months and work related symptoms of rhinitis, conjunctivitis, and asthma. All analyses were adjusted for age, sex, smoking, and atopy.

Results: The prevalence of work related asthma was 3.70% (95% confidence interval (95% CI) 2.88 to 4.52) and the prevalence of work related wheezing was 11.46% (95% CI 9.87 to 13.05). The main industries identified at risk of work related asthma and wheeze included the entertainment industry; agriculture, forestry, and fishing; construction; electrical machinery; repair services; and lodging places. The population attributable risk for work related asthma was 36.5% and work related wheezing was 28.5%.

Conclusions: The findings provide impetus for further research and actions by public health professionals which prioritise occupational asthma on the public health agenda. Future intervention strategies need to be developed for effective control and prevention of asthma in the workplace.