Unscheduled bleeding during initiation of continuous combined hormone replacement therapy: a direct comparison of two combinations of norethindrone acetate and ethinyl estradiol to medroxyprogesterone acetate and conjugated equine estrogens.

OBJECTIVE: To determine whether there are differences between continuous combined hormone replacement therapies on bleeding control. DESIGN: Nine hundred and forty-five postmenopausal women were randomized to one of seven double-blind treatment groups (placebo, 0.25 mg norethindrone acetate (NA)/5 microg ethinyl estradiol (EE), 1 mg NA/5 microg EE, 0.5 mg NA/10 microg EE, 1 mg NA/10 microg EE, 5 microg EE, and 10 micro EE) or unmasked 0.625 mg conjugated equine estrogens (CEE)/2.5 mg medroxyprogesterone acetate (MPA). Treatment was for 12 months; subjects kept daily diaries recording whether they had bleeding and/or spotting. RESULTS: The results focused on currently commercially available hormone replacement therapy products (femhrt [1 mg NA/5 microg EE] and Prempro [0.625 mg CEE/2.5 mg MPA]) as well as a high-dose NA/EE dose combination (1/10) over the first 6 months of use, the most critical period in establishing treatment adherence. At the end of month 6 there was a greater incidence of amenorrhea with both NA/EE dose combinations compared with CEE/MPA (p = 0.009 for 1 mg NA/5 microg EE and p = 0.006 for 1 mg NA/10 microg EE). Statistically significantly more women were amenorrheic at every month based on cumulative amenorrhea for 1 mg NA/5 microg (p < 0.05) compared with CEE/MPA; at months 3 and 6 more women were amenorrheic on 1 mg NA/10 microg EE compared with CEE/MPA using the cumulative amenorrhea parameter. CONCLUSIONS: The results indicate that statistically significantly more women attained amenorrhea based on various parameters when administered continuous combined NA/EE compared with CEE/MPA. The potential for long-term treatment compliance based on better bleeding control may optimize the opportunity to prevent osteoporosis as well as other associated health benefits.

Relationship of body composition measures and menstrual cycle length.

Menstrual cycle disruption has been observed in women with low body weight due to anorexia nervosa, or to athletics. However, the association of the full range of body composition measures with cyclicity has not been determined. Therefore, the purpose of this study was to determine the strength and direction of association between body composition measures (Quetelet Index, body fat mass, and body lean mass) and menstrual cycle length. Menstrual cycle diaries were distributed to women aged 24-45 in the Michigan Bone Health Study beginning in 1992. A total of 4392 menstrual cycles from 436 women were analysed from the first year of this ongoing study. Body composition measures (Quetelet Index or body mass index (kg/m2), body fat mass and body lean mass (kg) were obtained at annual clinic visits by means of dual-energy X-ray absorptiometry (DEXA). Mixed-model analyses were used to determine the degree of association between menstrual cycle length and body composition measures, controlling for age. There was a significant positive association with cycle length for each body composition measure. The relationship between each body composition measure and cycle length was nonlinear with the longest mean cycle lengths occurring with greater BMI, body fat mass or body lean mass. Longer cycle length was also noted at the lowest levels of BMI and body fat mass. These results may account for the purported later age at menopause for obese women.

Histologic classification and pathologic findings for endometrial biopsy specimens obtained from 2964 perimenopausal and postmenopausal women undergoing screening for continuous hormones as replacement therapy (CHART 2 Study).

OBJECTIVE: The aim of this study was to screen for disorders and to histologically classify endometrial biopsy specimens from 2964 perimenopausal and postmenopausal women who were candidates for hormonal replacement therapy. STUDY DESIGN: Endometrial biopsy specimens were obtained with a Vabra aspiration curette, processed by standard methods, and stained by hematoxylin and eosin and special methods to reveal subtle features of the endometrium. RESULTS: Of the endometrial biopsy specimens, 68.7% were atrophic, 23.5% were proliferative, 0.5% were secretory, 0.6% were hyperplastic, 0.07% were adenocarcinoma, and 6.6% were insufficient for classification. Three independent senior microscopists agreed on the classification of each biopsy specimen. CONCLUSION: The number of patients is the largest ever screened for a single hormone replacement therapy study. The low yield of endometrial cancer indicates that biopsies are unnecessary before hormone replacement therapy is initiated in asymptomatic women.

Tacrine hydrochloride treatment IND: methods for rapid physician and patient enrollment and data retrieval.

A Treatment IND (TIND) is a mechanism available to the Food and Drug Administration (FDA) in the United States by which promising new drugs can be provided to patients with life-threatening illnesses. In many instances, the illness is life-threatening but of relatively low incidence, making the demand for the new treatment limited. However, if the disease is more prevalent and incidence is increasing, the demand for access to an experimental therapy may be substantially greater. Novel approaches and technologies would help manage recruitment of physicians, enrollment of patients and retrieval and timely analysis of data. Such was the case in the TIND for tacrine hydrochloride (Cognex), a cholinesterase inhibitor which was under development for the treatment of patients with Alzheimer's Disease (AD). There were an estimated 4 million prevalent cases of AD in the US for which no approved therapeutic option was available at the time this TIND was initiated. We anticipated that there could be a large demand by both physicians and patients to enroll in the TIND. Therefore, to meet this demand, various mechanisms were employed to allow rapid enrollment and drug shipments to the patient. In addition, physicians who participated in the TIND were able to use a telephone touch-tone data entry system for reporting data and ordering new supplies of tacrine for their patients. Serious adverse events were reported directly to trained operators and summarized on a weekly basis for reporting to the FDA. At the time the programme was terminated, nearly 2000 physicians had enrolled to participate in the TIND and nearly 10,000 patients had received tacrine under the programme. The methods employed in this study to collect clinic visit and safety data met both regulatory and good clinical practice guidelines. In summary, a large volume of data was handled rapidly and efficiently in this programme.

Water-maze learning and effects of cholinergic drugs in mouse strains with high and low hippocampal pyramidal cell counts.

Morphological differences have been found in inbred strains of mice in the number and volume of pyramidal cells in Ammon's horn of the hippocampus. Among the mouse strains surveyed, NZB/BINJ (NZB) and C57BL/10J (B10) are most divergent in both total volume and total number of neurons. These genetically derived differences were exploited to determine hippocampal involvement in the acquisition of a spatial water maze. Genetic differences in hippocampal cell number were related to the acquisition of this spatial task. Mice with small numbers of hippocampal pyramidal cells, the B10 strain, acquired a water-maze task more slowly than either NZB mice or (NZBxNZW) F1 (NZBWF) animals. In addition, strain differences in responsivity to cholinergic manipulations were found. B10 mice were more sensitive than NZB or NZBWF mice to both the disruptive effects of scopolamine and the facilitory effects of physostigmine on swim maze learning. Although other inherited differences undoubtedly exist between these strains as is apparent in other mouse lines, these data suggest a prominent role for the hippocampus in the learning of spatially oriented behavior. Furthermore, this behavior appears to be responsive to cholinergic manipulations.

The effects of age and genotype upon the jaw-jerk reflex in inbred mice.

The threshold of the jaw-jerk reflex to electrical stimulation of the hard palate was measured in a cross-sectional design using C57BL/6J and DBA/2J mice at 2, 8, 20, 25, and 30 mo of age, in order to assess CNS sensitivity as a function of increasing age. The thresholds of DBA/2J mice were higher than those of C57BL/6J mice at all ages tested. No age-related changes in threshold were observed in mice of either strain.