Insulin sensitizers and polycystic ovary syndrome: can a diabetes medication treat infertility?
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Female↗
Biomedical subjects
A E Taylor
Publications and source records attributed to A E Taylor.
Identification of premature ovarian failure patients with underlying autoimmunity.
Although known causes of premature ovarian failure (POF) include X chromosome deletions, radiation and chemotherapy, and genetic defects of the gonadotropin hormones or receptors, at least one third to one half of cases remain idiopathic. A significant proportion of patients with apparently idiopathic POF have some evidence for an autoimmune etiology. However, the only gold standard for detecting autoimmune causes of immune ovarian destruction has been invasive ovarian biopsy. Serum antibodies to ovarian and other self-tissue have been described in up to one third of women with POF, but the tests are not well standardized, not well correlated with ovarian histology, and highly variable. Recently, specific defects of expression of cell surface markers on peripheral blood lymphocytes have been shown to identify, in population-based studies, individuals destined to develop autoimmune pancreatic destruction and type I diabetes mellitus, even before any other evidence of autoimmunity. We, therefore, sought to test the ability of cell surface marker expression in women with POF to identify autoimmune defects. Seventeen women with POF, 11 of whom had positive antibody titers to ovary, thyroid, or antinuclear antibody, were studied on at least two occasions and compared in blinded fashion with normal controls and patients with autoimmune type I diabetes mellitus. The most useful marker for identifying autoimmunity was the surface density of conformationally correct HLA class I molecules on macrophages, a structure essential for T cell education. Using this marker, 7 of the 9 patients with autoantibodies and 3 of the 8 patients without autoantibodies were identified as having evidence of a defect in self-antigen presentation similar to that of type I diabetics (chi-square, p = 0.03). Subsequent testing identified antismooth muscle antibodies in 1 of the women with a defect of HLA class I molecules but no previously identified autoimmunity. In addition, there were increased numbers of CD8 T cells in both autoimmune POF and insulin-dependent diabetes mellitus (IDDM) patients. Exclusive to POF patients was a statistically significant increase in CD8 density on T cells. This was most prominent in POF patients with an underlying autoimmune etiology. These data further support a role for autoimmunity in POF patients and suggest that the further development of cell surface markers in combination with other diagnostic tests could result in diagnosis before the development of complete ovarian failure. The possibility for disease-specific therapy to prevent further autoimmune ovarian damage in selected POF patients is also envisioned.
Adult↗
Responsiveness of common outcome measures for patients with low back pain.
STUDY DESIGN: A prospective cohort study assessing the responsiveness of two disease-specific questionnaires and a generic health questionnaire for patients with low back pain and sciatica. OBJECTIVES: To compare the responsiveness of the eight scales and two summery scales of the SF-36 questionnaire with that of the Oswestry Disability Index and Low Back Outcome Score questionnaires. SUMMARY OF BACKGROUND DATA: Evaluation of treatment outcome is being determined more frequently from a patient's perspective, particularly the impact treatment has on current health status. METHODS: Patients were recruited from two orthopedic back pain clinics in a tertiary hospital. Patients completed the pretreatment questionnaire 1 month before treatment and follow-up questionnaires a minimum of 2-6 months after treatment. Patients undergoing surgery were also observed for a minimum of 2 years. RESULTS: Overall, the Oswestry Disability Index was most responsive; however, individual scales from the SF-36 questionnaire showed equal or greater sensitivity to change than the Oswestry Disability Index in each of the patient subgroups. The SF-36 Role Physical scale was prone to floor effects (a high percentage of respondents score zero), and the change scores from the SF-36 Role Emotional scale varied by 100 points in either direction in each of the patient subgroups. CONCLUSION: Responsiveness varied according to which method was used in its calculation. The responsiveness of the SF-36 questionnaire shows that it can be a useful adjunct in the assessment of patients with low back pain when combined with disease-specific questionnaires.
Disability Evaluation↗
Observer error in grading performance status in cancer patients.
To assess the Karnofsky Performance Status (KPS) scale and the Eastern Cooperative Oncology Group (ECOG) scale with respect to interobserver reliability and interobserver difference between the two scales, 100 consecutive patients in a medical oncology unit were assessed using both scales, which were then given to three independent raters and also to the patients themselves. There was a high level of agreement between most paired assessors. There were three exceptions, which were the RMO/patient and nurse/patient pairs on the KPS scale and the RMO/patient pair on the ECOG scale. The level of agreement was better on the ECOG scale. For individual raters there is no statistical difference between the ECOG and Karnofsky scales. There was good agreement between all raters for both scales. Interobserver variability was less using the ECOG scale. We conclude that either scale could be used with good interobserver reliability. The ECOG scale minimises differences between observers.
Adolescent↗
Effects of attribution of responsibility for motor vehicle accidents on severity of PTSD symptoms, ways of coping, and recovery over six months.
In light of Delahanty et al.'s (1997) identification of attribution of responsibility for a motor vehicle accident (MVA) as a powerful determinant of initial level of distress from the trauma and of early remission of PTSD, we reexamined data from Blanchard and Hickling's (1997) prospective follow-up of 158 MVA survivors. Despite differences between the two samples (Delahanty sample recruited from hospitals 2-3 weeks post-MVA and predominantly male; our sample recruited from outpatient care 1-4 months post-MVA and predominantly female) we replicated Delahanty's findings: those with PTSD who blame themselves for the MVA are less symptomatic initially and recover more rapidly in the first 6 months than those with PTSD who blame another party for the accident.
Accidents, Traffic↗
Effects of short-term hormone replacement on serum leptin levels in postmenopausal women.
OBJECTIVE: Leptin is a hormone which is secreted by adipocytes and appears to influence the reproductive axis. Previous studies have demonstrated higher leptin levels in relation to body fat mass in women compared to men, higher levels in normally cycling compared to postmenopausal women, and a decrease in leptin levels with increased age. The purpose of this study was to determine whether oestrogen replacement with or without progesterone increases serum leptin levels in postmenopausal women, independently of changes in body fat, and to determine if ageing affects leptin levels at baseline or in response to hormone replacement. PATIENTS: Twenty-one healthy postmenopausal women on no hormone replacement were studied at baseline, after 1 month of oestrogen (E2: estraderm 50 microg/day) and after a further month of oestrogen and 7 days of progesterone (P: progesterone 100 mg per vagina bid) designed to achieve physiological hormone levels. Subjects included 11 younger (45-55 years) and 10 older (70-80 years) postmenopausal women. RESULTS: The relationship between leptin and the absolute fat mass (% body fat x weight [kg]) at baseline was not different between the younger and older postmenopausal women. The adequacy of physiological hormone replacement was confirmed in all subjects. Despite the absence of an effect of hormone replacement on weight, body mass index (BMI), % and absolute fat mass (bioimpedance) or waist-hip ratio, there was an increase in serum leptin levels with hormone replacement (15.4 +/- 1.7, 17.6 +/- 1.7, and 18.1 +/- 1.6 microg/l; mean +/- SEM at baseline, with E2, and with E2 + P, respectively; P < 0.001 vs. baseline) for the group as a whole. An increase in leptin with hormonal treatment was seen in both the younger (15.1 +/- 2.1, 18.1 +/- 2.4, and 18.5 +/- 1.9 microg/l; P < 0.01) and the older (15.7 +/- 2.8, 17.0 +/- 2.5, 17.7 +/- 2.8 microg/l; P = 0.06) postmenopausal women. CONCLUSIONS: (1) Short-term physiological oestrogen replacement increases serum leptin levels in postmenopausal women independently of changes in fat mass; and (2) physiological progesterone replacement does not influence leptin levels in postmenopausal women.
Adult↗
Cardiovascular responses to scorpion venom.
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Animals↗
Segmental microvascular permeability in ischemia-reperfusion injury in rat lung.
Segmental microvascular permeabilities were measured using pre- and postalveolar vessel capillary filtration coefficient (Kfc) values (ml. min-1. cmH2O-1. 100 g-1) in isolated rat lungs subjected to ischemia-reperfusion (I/R). Total Kfc values measured in flowing and nonflowing lungs were highly correlated (r = 0.98, P < 0.0001). Kfc values were then measured in another group of lungs under no-flow conditions when airway pressure was increased to 20 cmH2O and either the arterial or venous pressure was elevated to 7-8 cmH2O to measure the prealveolar and postalveolar Kfc values. Control total and postalveolar Kfc values were 0.0225 +/- 0.001 and 0.0219 +/- 0.001 ml. min-1. cmH2O-1. 100 g-1, respectively, and the prealveolar permeability was extremely small (0.00003 +/- 0.00005 ml. min-1. cmH2O-1. 100 g-1). Kfc values were again made in nonflowing lungs that had been subjected to 45 min of ischemia followed by 30 min of reperfusion. After I/R, the total membrane Kfc increased 10-fold to 0.2597 +/- 0.006 ml. min-1. cmH2O-1. 100 g-1, the prealveolar Kfc increased to 0.0677 +/- 0.003 ml. min-1. cmH2O-1. 100 g-1, and the postalveolar Kfc increased to 0.1354 +/- 0.008 ml. min-1. cmH2O-1. 100 g-1 (P < 0.05 for all I/R values). These data indicate that normal solvent microvascular permeability was predominantly postalveolar, and after I/R damage, the postalveolar (venular) permeability comprised 52% of the total, whereas the prealveolar and alveolar vessels comprised only 27 and 23%, respectively, of the total Kfc.
Animals↗
Capillary filtration coefficient, vascular resistance, and compliance in isolated mouse lungs.
Although many recently produced transgenic mice possess gene alterations affecting pulmonary vascular function, there are few baseline measurements of vascular resistance and permeability. Therefore, we excised the lungs of C57/BL6 mice and perfused them with 5% bovine serum albumin in RPMI-1640 culture medium at a nominal flow of 0.5 ml/min and ventilated them with 20% O(2)-5% CO(2)-75% N(2). The capillary filtration coefficient, a sensitive measurement of hydraulic conductivity, was unchanged over 2 h (0.33 +/- 0.03 ml. min(-1). cmH(2)O(-1). 100 g(-1)) in a control group ventilated with low peak inflation pressures (PIP) but increased 4. 3-fold after high PIP injury. Baseline pulmonary vascular resistance was 6.1 +/- 0.4 cmH(2)O. ml(-1). min. 100 g(-1) and was distributed 34% in large arteries, 18% in small arteries, 14% in small veins, and 34% in large veins on the basis of vascular occlusion pressures. Baseline vascular compliance was 5.4 +/- 0.3 ml. cmH(2)O(-1). 100 g(-1) and decreased significantly with increased vascular pressures. Baseline pulmonary vascular resistance was inversely related to both perfusate flow and microvascular pressure and increased to 202% of baseline after infusion of 10(-4) M phenylephrine due to constriction of large arterial and venous segments. Thus isolated mouse lung vascular permeability, vascular resistance, and the longitudinal distribution of vascular resistance are similar to those in other species and respond in a predictable manner to microvascular injury and a vasoconstrictor agent.
Animals↗
Female reproductive aging is marked by decreased secretion of dimeric inhibin.
The increase in serum FSH that accompanies female reproductive aging occurs before changes in estradiol (E2). A decrease in negative feedback from inhibin A (a product of the dominant follicle and corpus luteum) and/or inhibin B (secreted by developing follicles) may explain the rise in FSH with age. To test the hypothesis that decreases in inhibin A or inhibin B occur at an age at which the first increase in follicular phase FSH is evident, daily blood samples were obtained across the menstrual cycle from younger (<35 yr; n = 23) and older (35-46 yr; n = 21) cycling women. These cross-sectional studies were complemented by longitudinal data in 3 women studied at a 10-yr interval. In the early follicular phase, mean inhibin B was lower in older cycling women (88 +/- 7 vs. 112 +/- 10 pg/mL; P < 0.05) and FSH was higher (13.0 +/- 0.5 vs. 11.2 +/- 0.7 IU/L in older vs. younger, respectively; P < 0.04). In the mid- and late follicular phases, inhibin B was also lower in the older women (117 +/- 9 vs. 146 +/- 10 and 85 +/- 8 vs. 117 +/- 11 pg/mL; P < 0.04), whereas E2 was higher (105 +/- 14 vs. 68 +/- 5 and 240 +/- 27 vs. 163 +/- 9 pg/mL; P < 0.02), and no differences in FSH were observed in the two groups at these times. In women studied longitudinally, FSH and inhibin B varied inversely in the follicular phase. In the early luteal phase, mean inhibin B was lower in the older group (64 +/- 6 vs. 94 +/- 12 pg/mL; P < 0.03), and FSH was higher (12.5 +/- 1.0 vs. 9.7 +/- 0.6 IU/L; P < 0.03). In the mid- and late luteal phases, inhibin B was also lower in older subjects (21 +/- 2 vs. 33 +/- 5 and 22 +/- 2 vs. 36 +/- 6 pg/mL; P < 0.02). No difference in inhibin A, E2, or progesterone was observed across the luteal phase, between the two groups. However, in all subjects studied longitudinally, increased age was associated with a decrease in inhibin A, inhibin B, and progesterone in the absence of changes in E2. Our conclusions were: 1) reproductive aging is accompanied by decreases in both inhibin B and inhibin A; 2) the decrease in inhibin B precedes the decrease in inhibin A and occurs in concert with an increase in E2, suggesting that inhibin B negative feedback is the most important factor controlling the earliest increase in FSH with aging; 3) these studies suggest that the decrease in inhibin B is the earliest marker of the decline in follicle number across reproductive aging.
Adult↗
Impact of binge eating on metabolic and leptin dynamics in normal young women.
Well defined eating disorders such as anorexia nervosa and bulimia are associated with significant known health risks. Although binge eating behavior is increased in unsuccessfully dieting obese women, other health implications of this common eating pattern are unknown. We hypothesized that ingestion of an entire day's calories at one time in the evening, a common eating practice among Americans, would lead to disruptions in glucose, insulin, and leptin metabolism and in menstrual cyclicity, even in healthy young women. Seven lean women without a history of eating disorders were studied on two occasions separated by one or two menstrual cycles. During one admission, they ate three regular meals plus a snack on each of 3 days. On the other admission, they ate the same number of calories, macronutrient matched to the normal diet, in a single evening meal. Glucose, insulin, and leptin were measured frequently for 12-14 h beginning at 0800 h on the third day of each diet, and an insulin tolerance test was performed while the subjects were fasting on the fourth day. Daily blood samples were obtained until ovulation was documented to assess any impact on menstrual function. Ingestion of an entire day's calories at dinner resulted in a significant increase in fasting glucose levels and a dramatic increase in insulin responses to the evening meal. The diurnal pattern of leptin secretion was altered, such that the gradual rise in leptin from 0800 h observed during the normal diet was abolished, and leptin did not begin to rise during the binge diet until at least 2 h after the evening meal. No changes were demonstrated in insulin sensitivity, follicular growth, or ovulation between the two diets. We conclude that 1) ingestion of a large number of calories at one time (binge eating) impacts metabolic parameters even when total calories and macronutrients are appropriate for weight; 2) the timing of energy intake is an independent determinant of the diurnal rhythm of leptin secretion, indicating a relatively acute affect of energy balance on leptin dynamics; 3) the mechanism of exaggerated insulin secretion after a binge meal remains to be determined, but may be related to the altered diurnal pattern of leptin secretion; and 4) as most binge eating episodes in the population are associated with the ingestion of excess calories, it is hypothesized that binge eating behavior is associated with even greater metabolic dysfunction than that described herein.
Adult↗
A new contributing factor to polycystic ovary syndrome: the genetic variant of luteinizing hormone.
Although the etiology of polycystic ovary syndrome (PCOS) is still unclear, LH is considered to play a central role in its pathogenesis. An immunologically anomalous form of LH, with two point mutations in the LHbeta gene, has been recently described. This genetic variant of LH (v-LH), of wide geographic distribution, is functionally different from wild-type (wt) LH. To assess the role of the v-LH in PCOS, we analyzed its frequency in groups of PCOS patients from Finland, The Netherlands, the United Kingdom, and the United States. The LH status was determined by two immunofluorometric assays from a total of 1466 subjects. The carrier frequency of the v-LH allele in the whole study population was 18.5%, being highest (28.9%) in Finland and lowest (11.2%) in The Netherlands. In the individual countries, the frequency of v-LH was similar in obese and nonobese controls, but in The Netherlands and Finland, it was 5- to 7-fold lower in obese PCOS subjects compared with that in the other groups (2-4.5% vs. 10.3-33.3%; P < 0.05). A similar tendency was found in the United States (5.7% vs. 11.1-25.0%), but not in the United Kingdom. The overall high prevalence of v-LH in healthy women and women with PCOS suggests that it is compatible with fertility. The similar frequency of v-LH in healthy nonobese and obese women indicates that obesity per se is not related to the variant. In contrast, the lower frequency of v-LH in obese PCOS patients suggests that v-LH somehow protects obese women from developing symptomatic PCOS. However, the regional differences in this finding between patients with apparently similar diagnostic criteria emphasizes the multifactorial nature of this syndrome, and that its pathogenesis may vary according to the genetic background. Although the definitive role of v-LH in PCOS remains to be proven, its determination may improve the prediction of risk of PCOS, especially in obese women.
Adolescent↗
The Reproductive Endocrine Associates of the Massachusetts General Hospital: fifteen years of integrated clinical practice and investigation.
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Adult↗
The differential effects of cueing on recall in Parkinson's disease and normal subjects.
Patients with Parkinson's disease (PD) are known to be impaired in supraspan verbal learning due to reduced availability of internal encoding capacity. PD patients may suffer from poor semantic, source and sequential processing capacity. Thirty-three patients with idiopathic PD and 42 matched normal control subjects (NC) were administered the California Verbal Learning Test under 3 conditions of graded cueing. While the PD patients benefited significantly and progressively from increasingly explicit cueing, the NC group did not since their performance was optimal even without cueing. Results are discussed in relation to frontal executive control of attentional resources and the establishment of encoding strategies.
Aged↗
Insights into hypothalamic-pituitary dysfunction in polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) is characterized by menstrual dysfunction and hyperandrogenism in the absence of other known causes. While the pathogenesis of PCOS remains elusive and is likely to involve abnormalities in several systems, there has long been an association of abnormal gonadotropin secretion with this disorder. In recent studies we have determined that 94% of women meeting the broad criteria for PCOS have an increased LH/FSH ratio. Several lines of evidence suggest that the mechanisms underlying the increased LH/FSH ratio in PCOS include an increased frequency of GnRH secretion. Decreased sensitivity to progesterone negative feedback on the GnRH pulse generator may play a role in this neuroendocrine defect. Additional factors which may contribute to the low to normal FSH levels in the face of increased LH include chronic mild estrogen increases and possibly inhibin. In addition to these effects on the differential control of FSH, there is increased pituitary sensitivity of LH secretion to GnRH. Both estrogen and androgens have been proposed as candidates mediating these effects. Superimposed on these underlying abnormalities in gonadotropin secretion is a marked inhibitory effect of obesity on LH secretion which may be mediated at either a pituitary or hypothalamic level.
Female↗
Understanding the underlying metabolic abnormalities of polycystic ovary syndrome and their implications.
Women with polycystic ovary syndrome have an increased rate of obesity, with a propensity toward abdominal deposition of body fat. Independent of obesity, at least half of affected women have insulin resistance. To understand the mechanisms of insulin resistance in polycystic ovary syndrome, it is necessary to understand normal insulin signaling. Women with polycystic ovary syndrome have normal binding of insulin to its receptor but have decreased activation of events downstream of the receptor. This insulin resistance occurs mostly in the peripheral tissues (muscle and fat cells), and results in increased pancreatic insulin secretion to maintain normal glucose levels. Obese women with polycystic ovary syndrome have a relative defect in insulin secretion. At least 20% of obese patients with polycystic ovary syndrome have glucose intolerance or diabetes, versus about 5% of the healthy age-matched population. Obesity and insulin resistance probably increase the risk of cardiovascular disease in women with polycystic ovary syndrome. The metabolic features of polycystic ovary syndrome are important health risk factors and need to be considered seriously, even if the patient seeks treatment for other concerns.
Adipose Tissue↗
Polycystic ovary syndrome.
Polycystic ovary syndrome is a syndrome and not a disease. It reflects multiple potential etiologies and variable clinical presentations that are reviewed in this article. In addition to menstrual dysfunction and hyperandrogenism, women with polycystic ovary syndrome also may have hypothalamic-pituitary abnormalities, polycystic ovaries on pelvic ultrasonography, infertility, obesity, and insulin resistance. A familial pattern occurs in some cases, suggesting a genetic component to the disorder. The three major pathophysiologic hypotheses that have been proposed to explain the clinical findings of the disorder as well as treatment options are reviewed in this article.
Female↗