Detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III)

Population-based epidemiologic studies have uncovered the high prevalence and wide severity spectrum of undiagnosed obstructive sleep apnea, and have consistently found that even mild obstructive sleep apnea is associated with significant morbidity. Evidence from methodologically strong cohort studies indicates that undiagnosed obstructive sleep apnea, with or without symptoms, is independently associated with increased likelihood of hypertension, cardiovascular disease, stroke, daytime sleepiness, motor vehicle accidents, and diminished quality of life. Strategies to decrease the high prevalence and associated morbidity of obstructive sleep apnea are critically needed. The reduction or elimination of risk factors through public health initiatives with clinical support holds promise. Potentially modifiable risk factors considered in this review include overweight and obesity, alcohol, smoking, nasal congestion, and estrogen depletion in menopause. Data suggest that obstructive sleep apnea is associated with all these factors, but at present the only intervention strategy supported with adequate evidence is weight loss. A focus on weight control is especially important given the expanding epidemic of overweight and obesity in the United States. Primary care providers will be central to clinical approaches for addressing the burden and the development of cost-effective case-finding strategies and feasible treatment for mild obstructive sleep apnea warrants high priority.

Epidemiology of obstructive sleep apnea: a population health perspective.

Advances in flavonoid research since 1992.

Polyphenols are the most abundant antioxidants in the diet and are widespread constituents of fruits, vegetables, cereals, dry legumes, chocolate, and beverages, such as tea, coffee, or wine. Experimental studies on animals or cultured human cell lines support a role of polyphenols in the prevention of cardiovascular diseases, cancers, neurodegenerative diseases, diabetes, or osteoporosis. However, it is very difficult to predict from these results the effects of polyphenol intake on disease prevention in humans. One of the reasons is that these studies have often been conducted at doses or concentrations far beyond those documented in humans. The few clinical studies on biomarkers of oxidative stress, cardiovascular disease risk factors, and tumor or bone resorption biomarkers have often led to contradictory results. Epidemiological studies have repeatedly shown an inverse association between the risk of myocardial infarction and the consumption of tea and wine or the intake level of some particular flavonoids, but no clear associations have been found between cancer risk and polyphenol consumption. More human studies are needed to provide clear evidence of their health protective effects and to better evaluate the risks possibly resulting from too high a polyphenol consumption.

Dietary polyphenols and the prevention of diseases

Summary
BACKGROUND AND OBJECTIVE The original Whlckham Survey documented the prevalence of thyroid disorders in a randomly selected sample of 2779 adults which matched the population of Great Britain in age, sex and social class. The aim of the twenty-year follow-up survey was to determine the Incidence and natural history of thyroid disease in this cohort.

DESIGN, PATIENTS AND MEASUREMENTS Subjects were traced at follow-up via the Electoral Register, General Practice registers, Gateshead Family Health Services Authority register and Office of Population Censuses and Surveys. Eight hundred and twenty-five subjects (30% of the sample) had died and, In addition to death certificates, two-thirds had Information from either hospital/General Practitioner notes or post-mortem reports to document morbidity prior to death. Of the 1877 known survivors, 96% participated in the follow-up study and 91 % were tested for clinical, biochemical and Immunological evidence of thyroid dysfunction.

RESULTS Outcomes in terms of morbidity and mortality were determined for over 97% of the original sample. The mean Incidence (with 95% confidence Intervals) of spontaneous hypothyroidism in women was 3.5/1000 survivors/year (2.8-4.5) rising to 4.1/1000 survivors/year (3.3-5.0) for all causes of hypothyroidism and in men was 0.6/1000 survivors/year (0.3-1.2). The mean incidence of hyperthyroidism In women was 0.8/1000 survivors/year (0.5.1.4) and was negligible in men. Similar incidence rates were calculated for the deceased subjects. An estimate of the probability of the development of hypothyroidism and hyperthyroidism at a particular time, i.e. the hazard rate, showed an Increase with age In hypothyroidism but no age relation in hyperthyroidism.

The frequency of goitre decreased with age with 10% of women and 2% of men having a goitre at follow-up, as compared to 23% and 5% in the same subjects respectively at the first survey. The presence of a goitre at either survey was not associated with any clinical or biochemical evidence of thyroid dysfunction. In women, an association was found between the development of a goitre and thyroid-antibody status at follow-up, but not initially.

The risk of having developed hypothyroidism at follow-up was examined with respect to risk factors Identified at first survey. The odds ratios (with 95% confidence Intervals) of developing hypothyroidism with (a) raised serum TSH alone were 8 (3-20) for women and 44 (19-104) for men; (b) positive anti-thyroid antibodies alone were 8 (5-15) for women and 25 (10-63) for men; (c) both raised serum TSH and positive anti-thyroid antibodies were 38 (22-65) for women and 173 (81-370) for men. A loglt model Indicated that Increasing values of serum TSH above 2mU/l at first survey Increased the probability of developing hypothyroidism which was further Increased in the presence of anti-thyroid antibodies. Neither a positive family history of any form of thyroid disease nor parity of women at first survey was associated with Increased risk of developing hypothyroidism. Fasting cholesterol and triglyceride levels at first survey when corrected for age showed no association with the development of hypothyroidism In women.

CONCLUSIONS This historical cohort study has provided Incidence data for thyroid disease over a twenty-year period for a representative cross-sectional sample of the population, and has allowed the determination of the importance of prognostic risk factors for thyroid disease Identified twenty years earlier.

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The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey

The metabolic clearance rate (MCR) of human luteinizing hormone (hLH) has been determined in 10 normal men, 3 normal women, and in 12 women with ovulatory disorders resulting in oligomenorrhea or amenorrhea. The MCR was determined by the constant infusion technique using either iodinated or unlabeled highly purified hLH, and these results were compared to MCR determined by using crude pituitary preparations containing both follicle-stimulating hormone and hLH. Both preparations produced essentially similar results for the MCR of hLH and virtually identical results were obtained when complete or incomplete immunoprecipitation of the infused material was achieved. The MCR/body surface area of hLH was significantly greater in normal men (25.6 plus or minus 3.6 ml/min-m-2) than in normal premenopausal (19.2 plus or minus 0.9 ml/min-m-2) or postmenopausal women (17.4 plus or minus 1.9 ml/min-m-2). No difference was noted in the MCR of hLH in women with oligomenorrhea or amenorrhea. Production rates (PRs) were calculated by using a pituitary standard, the values being 85.1 plus or minus 21.5 IU/24 h in normal men, 39.9 plus or minus 12.6 IU/24 h in normal premenopausal women, and 294.6 plus or minus 61.9 IU/24 h in normal postmenopausal women. The initial half-times of disappearance of the alpha- and beta-subunits of hLH were measured in two normal men and found to be 15-18 min, respectively. The half-time of intact hLH was twice as great.

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Studies on the metabolic clearance rate and production rate of human luteinizing hormone and on the initial half-time of its subunits in man.

In order to determine whether serum-immunoreactive inhibin could constitute a biochemical marker for the presence and progression of ovarian granulosa cell tumors and their metastases, we measured immunoreactive inhibin concentrations in series of serum samples obtained from 8 patients with granulosa cell tumor. Six series were tested in retrospect. From these, three came from patients who had been treated with an abdominal hysterectomy and bilateral salpingo-oophorectomy. In the 2 patients with residual or recurrent disease, inhibin was elevated, 4 and 20 months respectively before clinical manifestations of recurrence became evident; it reflected the effects of secondary therapy. Inhibin remained undetectable in one patient who was free of disease during 11 years of follow-up. Inhibin concentrations were also inappropriately increased in 2 of 3 women with amenorrhea and infertility resulting from small granulosa cell tumors. After removal, inhibin concentrations became normal and fertility resumed. Fertility also returned in the third patient. There was a significant negative correlation between the serum inhibin and FSH concentrations, consistent with autonomous production of inhibin by granulosa cell tumors. It is concluded that granulosa cell tumors have the capacity to produce inhibin. In retrospect, inhibin proved to be a marker for both primary and also recurrent and residual disease.

Inhibin as a marker for granulosa cell tumor.

The discovery of a new hormone is understandably followed by a competitive urgency to seek useful clinical applications. For the glycoprotein hormones inhibin, isolated in 1985 (Ling et al ., 1985; Robertson et al ., 1985), and activin, identified the following year (Vale et al ., 1986), this is no exception. Some 15 years on, we aim to summarize the advances made in understanding the roles of inhibins and activins in human reproduction, and review their current and likely future applications in clinical practice. Inhibins are heterodimeric glycoprotein hormones comprising a common α -subunit and one of two β -subunits ( α β A forming inhibin A, α β B forming inhibin B). Other β -subunits have been identified, but there is currently no evidence for the existence of additional biologically active inhibin species (Burger et al ., 2000). The existence of inhibin was predicted by McCullagh almost 70 years ago, who noted that hypertrophy of the anterior pituitary gland caused by castration could be prevented by injecting a water soluble extract of bovine testis (McCullagh, 1932). However, McCullagh’s ‘inhibin’ hypothesis remained stalled for half a century, until the 1970s, when it was found that FSH from the pituitary gland could be selectively suppressed both in vitro and in vivo by testicular (Franchimont et al ., 1972; Setchell & Jacks, 1974; Keogh et al ., 1976) and follicular fluids (De Jong & Sharpe, 1976). It would take another decade until inhibin was finally isolated and characterized from bovine (Robertson et al ., 1985) and porcine (Ling et al ., 1985) follicular fluid. During the purification of inhibin, a structurally related substance which stimulated FSH secretion was identified. This substance was termed activin (Vale et al ., 1986) and is a dimer of the inhibin β subunit. Three activins exist: activin A ( β A – β A ), activin B ( β B – β B ) and activin AB ( β A – β B ). Inhibins and activins are related to the transforming growth factor beta (TGFβ ) superfamily, sharing structural homology through the β subunit as well as common receptor pathways (Derynck et al ., 1998). Not surprisingly, it has become clear that, in addition to the regulation of FSH secretion, activins and inhibins may have diverse actions in varied tissues, including autocrine regulation of cell proliferation in the male reproductive tract (Risbridger & Cancilla, 2000), erythropoiesis (Yu et al ., 1987) and neural cell survival (Schubert et al ., 1990). Some recent advances in the understanding of activin and inhibin signalling have occurred recently with the identification of two possible inhibin receptors (Chong et al ., 2000; Lewis et al ., 2000). However, full consideration of these findings and the activin receptors and signalling mechanisms is outwith the scope of this review and is available elsewhere (Mathews, 1994; Heldin et al ., 1997; Derynck et al ., 1998; Attisano & Wrana, 2002). While initially problematic, the eventual purification of inhibin led rapidly to the development of a number of immunoassays (Burger, 1993), the most widely used of which was a radioimmunoassay employing a polyclonal antibody raised against purified bovine inhibin, with specificity directed against an epitope on the α subunit (McLachlan et al ., 1986a). This assay became known as the ‘Monash’ assay and was the basis of almost all of the initial studies of inhibin in human reproductive pathophysiology. However, it became apparent that this assay also detected circulating α -subunit free from the β -subunit and of uncertain bioactivity (Schneyer et al ., 1990). Therefore, while the application of the Monash assay led to important advances in our understanding of inhibin in reproductive physiology, some observations, as will be discussed below, were difficult to explain (Bhasin et al ., 1996). The subsequent development of specific two site assays, particularly those peformed by Groome and colleagues (Groome et al ., 1994, 1996), for inhibin A and B, inhibin α -subunit precursors and the activins, clarified those apparent inconsistencies and revealed the specific changes in inhibins and activins in health and disease, as discussed below. Although there are a host of different areas of investigation into inhibins and activins in obstetrics and gynaecology, they centre around three major tissues of origin: the ovary, placenta and testis. Therefore, this review will be structured around these sites of origin, affording a logical discussion linking clinical studies to the physiology of these hormones.

Inhibins and activins: clinical advances in reproductive medicine

This paper examines the relationship between well-being, age, menopausal status, hormone levels and hot flashes. Data from the first 4 years of longitudinal observation from the Melbourne Women's Midlife Health project was utilized. This study involved a population-based sample of 405 women interviewed annually. Blood was taken during the follicular phase (if still menstruating) for estradiol, sex hormone binding globulin, follicle stimulating hormone and testosterone. A validated well-being scale was used. Positive affect increased with age while negative affect decreased with age but only in the postmenopausal category. Positive affect was significantly lower in the 2 years postmenopausal group but this effect of menopausal status did not remain when hot flashes were included in the analysis. Negative affect was highest in the 1–2 years postmenopausal group. Although hot flashes adversely affected negative moods, a significant effect of menopausal status remained. No direct association between any of th...

Henry G. Burger

Papers

Studies on the metabolic clearance rate and production rate of human luteinizing hormone and on the initial half-time of its subunits in man.

Inhibin as a marker for granulosa cell tumor.

Inhibins and activins: clinical advances in reproductive medicine

Well-being and the menopausal transition.

Thyrotrophin releasing hormone--TSH.