News and views in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): The role of co-morbidity and novel treatments.

Though affecting many thousands of patients, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) should be considered an orphan disease, since the cause remains elusive and no treatment is available that can provide complete cure. There is reasonable insight into the pathogenesis of signs and symptoms, and treatments specifically directed to immunological, inflammatory and metabolic processes offer relief to an increasing number of patients. Particular attention is given to the importance of co-morbidity requiring appropriate therapy. Promising results are obtained by treatment with Metformin, or possibly Momordica charantia extract, which will correct insulin resistance, with Meldonium improving the transportation of glucose into the mitochondria, with sodium dichloroacetate activating pyruvate dehydrogenase, and with nutraceutical support reducing oxidative and inflammatory impairment.

Apolipoprotein B-48 is the product of a messenger RNA with an organ-specific in-frame stop codon.

The primary structure of human apolipoprotein (apo) B-48 has been deduced and shown by a combination of DNA excess hybridization, sequencing of tryptic peptides, cloned complementary DNAs, and intestinal messenger RNAs (mRNAs) to be the product of an intestinal mRNA with an in-frame UAA stop codon resulting from a C to U change in the codon CAA encoding Gln2153 in apoB-100 mRNA. The carboxyl-terminal Ile2152 of apoB-48 purified from chylous ascites fluid has apparently been cleaved from the initial translation product, leaving Met2151 as the new carboxyl-terminus. These data indicate that approximately 85% of the intestinal mRNAs terminate within approximately 0.1 to 1.0 kilobase downstream from the stop codon. The other approximately 15% have lengths similar to hepatic apoB-100 mRNA even though they have the same in-frame stop codon. The organ-specific introduction of a stop codon to a mRNA appears unprecedented and might have implications for cryptic polyadenylation signal recognition and RNA processing.

Amino acid substitutions in the DNA-binding domain of the human androgen receptor are a frequent cause of receptor-binding positive androgen resistance.

In some subjects with genetic and endocrine evidence of androgen resistance, no defect is demonstrable in the binding of androgen to its receptor in cultured genital skin fibroblasts. We have defined the molecular defect in the androgen receptor in four unrelated subjects in this category (termed receptor positive) with the phenotype of compete or incomplete testicular feminization. In these patients we detected amino acid substitutions in either exon 2 or exon 3, which encodes the DNA-binding domain of the androgen receptor. In one patient with incomplete testicular feminization, two separate mutations were present in exon 3. Introduction of these amino acid substitutions into the androgen receptor-coding segment leads to the expression of receptor proteins that bind ligand in a normal fashion but do not activate the transcription of the androgen-responsive mouse mammary tumor virus promoter. Mobility shift assays using androgen receptor fusion proteins produced in E. coli indicate that these mutations impair binding of the receptor to specific DNA sequences. In the subject with incomplete testicular feminization, a Ser-Gly substitution at amino acid residue 595 is able to partially restore DNA-binding activity to a mutant receptor protein that carries an Arg-Pro substitution at position 615. These findings indicate that mutations in amino acid residues crucial to the binding of the androgen receptor to target DNA sequences are a common cause of receptor-binding positive androgen resistance and that variable impairment of DNA binding can lead to distinctive phenotypes.

Leydig cell function in normal men: effect of age, life-style, residence, diet, and activity.

The decrease of plasma testosterone (T) in old age may be inherent to the aging process or secondary to environmental factors such as stress, minor illness, physical inactivity, etc. We determined plasma T, apparent free T, and gonadotropin levels in healthy men (n = 71), aged 26-90 yr living under identical conditions, i.e. as monks in a monastery. We found a highly significant age-dependent decrease in morning and mean 24-h T and apparent free T levels and a moderate increase in gonadotropin levels; the nycthemeral variation in plasma levels was, however, decreased in the elderly. In a larger group of healthy normal men (n = 302), smokers had higher T levels than nonsmokers in all age groups; values were similar whether older men lived in a geriatric institution or in their home. Diet had no discernable effect on T levels, whereas in young men plasma T levels decreased more in response to stress such as hypoglycemia or myocardial infarction than in elderly subjects. Moderate physical training in men, convalescing from myocardial infarction, did not alter consistently plasma T levels. We conclude that the age-associated decrease in plasma T levels is inherent to the aging process.

Influence of age on steroid concentrations in skin and striated muscle in women and in cardiac muscle and lung tissue in men.

In order to investigate whether androgen concentrations vary as a function of age in all tissues and organs and whether the sexual differences in plasma androgen levels are reflected in tissue concentrations, testosterone (T), 5 alpha-androstane-17 beta-ol, 3-one (DHT), 5 alpha-androstane-3 alpha,17 beta-diol (Adiol), and 4-androstene-3,17-dione (Adion) concentrations were measured postmortem in lung tissue and myocardium of men aged 16-87 yr. The results were compared to values obtained previously in other tissues. Similar measurements were made in various tissues (labia majora, clitoris, pubic skin, thigh skin, striated muscle) from women aged 16-87 yr. In cardiac tissue of men, T was quantitatively the most important androgen and concentrations of DHT and Adiol were low, reflecting low 5 alpha-reductase activity; in lung tissue, T and Adion were found in similar concentrations, with lower levels of 5 alpha-reduced metabolites. In both cardiac and lung tissue, androgen concentrations decreased significantly with age. In women, androgen concentrations were highest in specific androgen target tissues (labia majora, clitoris) and lowest in thigh skin and striated muscle. The ratios of the 5 alpha-saturated metabolites (DHT plus Adiol) to T or to T + Adion, respectively, parallel total androgen concentrations, whereas the Adiol to DHT ratio, a parameter of 3 alpha-reductase activity, was highest in striated muscle and thigh skin and lowest in androgen target tissues (labia majora and clitoris). In women tissue concentrations of all androgens decreased significantly with age in nearly all tissues studied. As expected tissue androgen concentrations were lower in women than in men, but in androgen target tissues such as the clitoris or labia majora, concentrations were little lower than in scrotal skin. We conclude that in both men and women androgen target tissues contain high androgen concentrations and high 5 alpha-reductase activity; moreover androgen concentrations in target tissues are similar in both sexes. In both sexes tissue androgen concentrations decreased with age in most tissues, but in target tissues the decrease was more pronounced in women than in men.

Aging and tissue androgens.

Testosterone, 5 alpha-androstane-17 beta-ol-3-one (DHT) and 5 alpha-androstane-3 alpha,17 beta-diol (Adiol) concentrations were measured in postmortem tissues (pubic skin, scrotal skin, thigh skin, and striated muscle) from 24 males, aged 20-82 yr. Androgen concentrations were highest in scrotal skin, followed by those in pubic skin, and lowest in thigh skin and striated muscle. Moreover, using the ratio of DHT plus Adiol over testosterone as a parameter of 5 alpha-reductase activity, the following order, from highest to lowest activity, was found: scrotal skin greater than pubic skin greater than thigh skin greater than striated muscle. If the Adiol over DHT ratio was taken as a parameter of 3-reductase activity, then this order, from highest to lowest activity, was: striated muscle greater than thigh skin greater than pubic skin greater than scrotal skin. An age-dependent decrease in androgen concentration was only found in pubic skin. The unexpected absence of such a decrease in scrotal skin might be explained by the embryological origin of the scrotum, which is similar to that of the prostate, an organ which also does not show any age-dependent decrease in androgen concentration. In the other tissues, this absence might be related to the relatively low concentration, high individual variability, and small number of subjects studied.

Fat tissue: a steroid reservoir and site of steroid metabolism.

Sex steroid concentrations and 17 beta-hydroxy-steroid dehydrogenase and aromatase activities were determined in fat tissue removed at surgery or, in order to allow comparisons in different sites, postmortem. Except for dehydroepiandrosterone (DHEA) sulfate (DHEAS), there existed a positive tissue/plasma gradient for all steroids studied (testosterone, androstenedione, DHEA, androstenediol, estrone, and estradiol), suggesting androgen uptake and estrogen synthesis in situ. Androgen concentrations did not vary according to site of origin of fat tissue, except that the DHEAS concentration was significantly lower in abdominal sc and omental fat than in breast, pericardial, or sc pubic fat. Tissue androgen concentrations were positively correlated with their plasma concentrations, but tissue and plasma estrogen concentrations were not correlated. All tissue steroid concentrations, with the exception of estradiol in men, decreased with age. Aromatase activity [androstenedione----estrone; mean maximum velocity, 7.4 +/- 3.7 (+/- SD) fmol estrone/mg protein . h] did not vary between sexes or with site of origin of fat tissue. 17 beta-Hydroxysteroid dehydrogenase activity (estradiol----estrone, mean maximum velocity 9.8 +/- 5.4 pmol/mg protein . h) was higher in fat from women than in that from men, higher in premenopausal than in postmenopausal women, and higher in omental than in sc fat. Its activity was noncompetitively inhibited in vitro by DHEA and DHEAS in near-physiological concentrations, and the enzyme activity was inversely correlated (P less than 0.001) with the tissue DHEA and DHEAS concentrations. We conclude that fat tissue is an important steroid hormone reservoir, that it is the site of active aromatase and 17 beta-hydroxysteroid dehydrogenase, and that tissue DHEA(S) may have a modulating effect on tissue estrogen production.

Influence of antiopioids on luteinizing hormone pulsatility in aging men.

To investigate whether changes in opioid tone play a role in the age-associated changes in LH release in men, the influence of an antiopioid, naltrexone, on plasma LH levels and LH pulses was studied in a group of young and elderly normal men. The young and elderly men had similar basal LH pulse frequencies, but the frequency of high amplitude (greater than 2 IU/L) LH pulses, mean LH pulse amplitude, maximal LH pulse amplitude and pulse area, were lower in the elderly men. Naltrexone administration (40 mg at 0630 and 2200 h the day before blood sampling and at 0630 h, 30 min before starting frequent blood sampling at 10-min intervals for 12 h) to young men (n = 8) induced a significant increase in individual mean baseline plasma LH levels, LH pulse frequency, and the sum of LH pulse amplitudes. In elderly men (n = 11) only a borderline significant increase in baseline plasma LH levels occurred, and neither LH pulse frequency nor the sum of the amplitudes of LH pulses increased. We suggest that in elderly men either opioid tone or the response of the gonadotrophs to endogenous LHRH is decreased.

Adrenocortical function in old age: response to acute adrenocorticotropin stimulation.

To elucidate the controversial point whether, in analogy with delta 5-steroid secretion, adrenal delta 4-steroid secretion is significantly decreased in elderly persons, we studied the response of plasma levels of both delta 5-steroids (dehydroepiandrosterone, 17-hydroxypregnenolone, and pregnenolone) and delta 4-steroids (cortisol, androstenedione, 17-hydroxyprogesterone, and progesterone) to acute ACTH stimulation in four groups of young and elderly males and females, respectively. To study the possible influence of sex hormones on adrenocortical function in elderly persons, we performed the same study in male with prostatic carcinoma treated with estrogens. The data show that in elderly persons, the response of plasma delta 4-steroids to ACTH stimulation is comparable or higher than that in young subjects, whereas the response of delta 5-steroids is significantly decreased; estrogen treatment does not change this pattern. It is concluded that in elderly persons adrenal delta 4-steroid secretory capacity is unimpaired, whereas delta 5-steroid secretion is significantly decreased. The responsible mechanism remains to be elucidated.

Attenuated luteinizing hormone (LH) pulse amplitude but normal LH pulse frequency, and its relation to plasma androgens in hypogonadism of obese men.

To evaluate the effects of obesity on the hypothalamo-pituitary-testicular axis, we compared total and free (FT) testosterone (T), androstenedione, dehydroepiandrosterone and its sulfate, and 5 alpha-androstane-3 alpha, 17 beta-diol glucuronide, and estradiol levels in a group of 35 obese [body mass index (BMI), > 30] men (aged 17-61 yr) to levels in a nonobese control group. We observed a highly significant negative correlation (P < 0.001) between plasma (F)T levels and BMI and a significant positive correlation (P < 0.01) between E2 levels and BMI. There were no differences between the obese and the nonobese men in levels of androstenedione, dehydroepiandrosterone sulfate, and 5 alpha-androstane-3 alpha, 17 beta-diol glucuronide. Insulin levels were significantly higher in obese men and were significantly (P < 0.02) correlated with the waist hip girth ratio. To evaluate the role of the hypothalamo-pituitary complex in the decreased (F)T levels in obese men, diurnal (0800-2000 h) LH pulsatility was studied in eight obese middle-aged men and eight age-matched controls. The pulsatility of plasma cortisol levels was also studied. Whereas LH pulse frequency was similar in the obese and control subjects, mean diurnal LH levels, mean diurnal LH pulse amplitude, and the sum of all diurnal LH pulse amplitudes and secretory masses were significantly lower in the obese than in the controls. Moreover, there was a highly significant correlation between the sum of LH pulse amplitudes and plasma (F)T levels. This decrease in LH pulse amplitude is not an isolated phenomenon of hypothalamo-pituitary dysfunction in obese men, because the pulse amplitude of plasma cortisol levels was also decreased. The decreased LH pulse amplitude together with the normal respond of Leydig cells to hCG stimulation reported in the literature suggest by inference that the decreased FT levels in obese men are the consequence of a hypogonadotropism. The decreased LH pulse amplitude and the decreased amplitude of cortisol pulses, and hence probably of ACTH pulses, point toward a general alteration of hypothalamo-pituitary function in obese men.

Influence of age on pulsatile luteinizing hormone release and responsiveness of the gonadotrophs to sex hormone feedback in men.

The influence of aging on serum LH and testosterone (T) pulse frequency and gonadotroph sensitivity to androgen and estrogen feedback was studied in young (less than 55 yr old) and elderly (greater than 65 yr) Trappist monks. LH pulse frequency (sampling interval, 20 min) was significantly lower [0.25 +/- 0.03 (+/- SEM) vs. 0.38 +/- 0.02 pulses/h; P less than 0.01] in elderly (n = 21) than in young monks (n = 27); the pulse amplitudes were similar. Similarly, T pulse frequency was lower in the elderly than in the young monks (0.13 +/- 0.04 vs. 0.23 +/- 0.02 pulses/h; P less than 0.01). In elderly men, the hypothalamo-pituitary complex was more sensitive to 5 alpha-androstan-17 beta-ol-3-one feedback, as determined by the decrease in serum LH and T levels. Moreover, during 5 alpha-androstan-17 beta-ol-3-one (125 mg/day, percutaneously, for 10 days) administration, the LH response to LHRH (100 micrograms, iv) was significantly higher in the elderly men compared to the pretreatment response. During estradiol (1.5 mg/day, percutaneously for 10 days) administration, the LH response to LHRH was decreased in the elderly men, but unchanged in the young men, suggesting greater responsiveness to estradiol in the elderly men. We conclude that in aged men, decreased testicular androgen secretion is not exclusively the consequence of a primary testicular alteration, but that important changes occur in hypothalamo-pituitary function, specifically decreased LH pulse frequency and increased LH responsiveness to sex hormone feedback.

Comparison of plasma androgen glucuronide levels after percutaneous or peroral androgen treatment in men: evidence for important splanchnic contribution to plasma 17 beta-hydroxyandrogen glucuronides.

To investigate whether glucuronides of 17 beta-hydroxyandrogens are formed mainly in peripheral tissues or in splanchnic tissues, we compared androstanediol (AD) glucuronide (ADG) and dihydrotestosterone (DHT) glucuronide (DHTG) levels as well as the ratios of glucuronides over free steroids after transcutaneous DHT gel administration to levels and ratios found after oral administration of testosterone undecanoate. Whereas DHT and AD plasma levels were much higher after transcutaneous DHT gel administration, ADG and DHTG levels as well as glucuronide/free androgen ratios were an order of a magnitude higher after oral TU. This indicates that 17 beta-hydroxyandrogen glucuronides cannot be considered specific metabolites of androgen target tissues and are formed to a large extent in the splanchnic circulation.

Stability of n-3 fatty acids in human fat tissue aspirates during storage.

The content of n-3 (omega 3) polyunsaturated fatty acids in fat tissue is an indicator of their long-term consumption. Therefore, a method for determining n-3 fatty acids in human fat tissue microbiopsies was validated and the stability of n-3 fatty acids in biopsies was checked under various conditions of storage. Methyl esters were prepared from 25 to 35 mg adipose tissue and separated by capillary gas chromatography. Recovery of added eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) was 98-105%. The change after storage of fat samples at room temperature or at 4, -20, or -80 degrees C for 3 mo averaged +3.3% for EPA and +2.1% for DHA, with no effect of temperature. Storage at +20 or -80 degrees C for 7 mo yielded no perceptible change in EPA, DHA, or five other n-3 polyunsaturated fatty acids. EPA and DHA concentrations in adipose tissue aspirates are remarkably stable and deserve attention as biomarkers in epidemiological studies.

Discriminative value of lipids and apoproteins in coronary heart disease.

Serum cholesterol, HDL cholesterol (HDL-C), and apoproteins, A1, A2 and B were determined in 70 male survivors of myocardial infarction and in an equal number of healthy controls, matched for age, sex and body mass index. In univariate analyses, the Apo B/Apo A1 ratio discriminated the best between cases and controls, giving a 72% exact classification. In a multivariate analysis, the Apo B/Apo A1 ratio, HDL-C and the Apo A2/Apo A1 ratio contributed independently to the discrimination of cases from controls while the overall exact classification was 82%. These promising results were comparable in younger and older subgroups. Thus, the determination of apoproteins yielded complementary information in this cross-sectional survey and warrants further study in a prospective setting.

Lipids and coronary heart disease in Asia.

In Western countries, it has been shown that coronary heart disease (CHD) is related to high serum total cholesterol (TC) levels. In less developed continents such as Asia and Africa, serum lipid levels are low and CHD incidence is much lower as compared with Western countries. With growing urbanization and industrialization in Asia, it has been shown that there is a concomitant rise in the level of serum TC and with it a rise in CHD. In all the Asian countries, serum TC levels are also higher in the urban compared with the rural population. Singapore, the only Asian country which is 100% urbanized since 1980, showed a rise of serum TC similar to that seen in the US and UK from the 1950s to the 1980s followed thereafter by a fall. This is reflected in the trend (rise followed by a fall) of CHD morbidity and mortality as well. In spite of a declining trend in serum TC level, CHD morbidity and mortality are still high in Singapore and comparable to the Western countries. The rest of the Asian countries show a different pattern from Singapore. In general, there is still a rising trend in serum TC level and in CHD mortality in most Asian countries. However, Japan is considered an exception in having a decreasing CHD mortality in spite of an increasing trend in serum TC. This may be attributed to a better control of other CHD risk factors such as hypertension and smoking. The rising trend in serum TC level remains a cause for concern, as this will emerge as a major problem for CHD morbidity and mortality in the future.

Body fat distribution in relation to serum lipids and blood pressure in 38-year-old European men: the European fat distribution study.

A study on 512 38-year-old European men selected from 6 different towns was conducted. There were significant differences between the centers in averages of anthropometric variables (except for thigh circumference), serum lipids (except for LDL-cholesterol), and blood pressure. In the pooled material, body mass index (BMI) as well as waist circumference, waist/hip ratio and waist/thigh ratio and subscapular skinfold were positively correlated to serum triglycerides, total cholesterol, LDL-cholesterol, and blood pressure and negatively with HDL-cholesterol. After adjustment for BMI, waist, waist/hip, and waist/thigh were all still significantly correlated with serum triglycerides (P less than 0.001). In addition, waist/hip and waist/thigh ratio showed significant partial correlations with total cholesterol (r = 0.16, P less than 0.001, r = 0.10, P less than 0.05 respectively), and diastolic blood pressure (r = 0.10, P less than 0.05, r = 0.09, P less than 0.05 respectively). In addition, waist/hip was, independently of BMI, correlated to LDL-cholesterol (r = 0.12, P less than 0.01), and waist/thigh ratio with HDL-cholesterol (r = -0.12, P less than 0.01). The partial association between waist/thigh with HDL cholesterol became insignificant after adjustment for smoking habits and physical activity. Adjustment for differences in anthropometric measurements did not explain the differences in serum lipids and blood pressure between the centers. The authors conclude that indicators of body fat distribution are associated with unfavorable risk profiles for cardiovascular disease in European men covering a large geographical and cultural variety and a wide range of body measurements and cardiovascular risk factors.

Clinical implications of the biopharmaceutical properties of fluvastatin.

Fluvastatin sodium (Lescol; Sandoz) the first entirely synthetic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor studied, is structurally distinct from the other HMG-CoA reductase inhibitors currently available, all of which are fungal metabolites and analogues of compactin. Fluvastatin's distinct structure may be responsible for the biopharmaceutical properties that result in its low systemic exposure and, subsequently, low incidence of peripheral adverse events, such as headache and myositis. Fluvastatin is rapidly absorbed from the gastrointestinal tract; has a 30-minute half-life, the shortest of any currently available HMG-CoA reductase inhibitor (lovastatin, 15 hours; pravastatin, 2 hours; simvastatin, 15.6 hours); is highly selective for the liver, undergoing extensive first-pass metabolism; has no active circulating metabolites; and does not penetrate the blood-brain barrier, unlike lovastatin and simvastatin. The low systemic exposure suggests that the occurrence of peripheral adverse events, such as myositis, central nervous system effects, and drug-drug interactions, may be less than what is currently observed with other HMG-CoA reductase inhibitors. Neither niacin nor propranolol had an effect on fluvastatin plasma levels when combined with fluvastatin. In contrast to other HMG-CoA reductase inhibitors, fluvastatin in combination with niacin resulted in no instances of myositis or other serious adverse events. Although the interaction of fluvastatin with cholestyramine resulted in a lower rate and extent of fluvastatin bioavailability, this reduction had no impact on clinical efficacy. Fluvastatin administered to patients chronically receiving digoxin had no effect on the area under the curve (AUC) of digoxin compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Testosterone and 5 alpha-dihydrotestosterone interact differently with the androgen receptor to enhance transcription of the MMTV-CAT reporter gene.

Testosterone and its 5 alpha-reduced derivative 5 alpha-dihydrotestosterone exert different actions in the male during embryogenesis and in postnatal life. Nevertheless the two hormones bind to the same intracellular androgen receptor, and genetic and endocrinological studies in the Tfm mouse suggest that the actions of both hormones are mediated by this single receptor. Previous studies indicate that dihydrotestosterone binds more tightly to the androgen receptor but that the Bmax of binding of the two hormones is the same. To determine whether these differences in binding parameters could explain the mechanism by which the two hormones exert different physiological actions via the same receptor, we introduced a plasmid encoding the androgen receptor cDNA and a reporter plasmid encoding MMTV-CAT into Chinese hamster ovary cells. These cells do not express endogenous androgen receptor and do not convert testosterone to dihydrotestosterone. Therefore, it was possible to examine the relation between the concentration of each of the steroids and reporter gene expression. Both hormones enhanced CAT activity, but dihydrotestosterone was approximately 10 times as potent (half maximal of 0.018 nM) as testosterone (half maximal of 0.2 nM); the maximal activity achieved was the same for the two androgens. These findings are nearly identical to the apparent Kd values for the interaction of the two hormones with the androgen receptor. Although testosterone and dihydrotestosterone may influence the expression of other genes differently, these findings are compatible with a model system in which the differential effects can be explained as a consequence of different binding affinities to the receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuroendocrine regulation of pulsatile luteinizing hormone secretion in elderly men.

Leydig cell function is driven by LH, secreted in a pulsatile manner by the anterior pituitary in response to episodic discharge of hypothalamic LHRH into the pituitary portal circulation, under control of a yet to be defined neural mechanism, the "hypothalamic LHRH pulse generator". The normal aging process in elderly men is accompanied by a decline in Leydig cell function. Whereas primary testicular factors undoubtedly play an important role in the decrease of circulating (free) testosterone levels with age, recent studies demonstrated that aging also affects the central compartment of the neuroendocrine cascade. Hypothalamic alterations comprise changes in the regulation of the frequency of the LHRH pulse generator with an inappropriately low frequency relative to the prevailing androgen impregnation and opioid tone, and with an increased sensitivity to retardation of the LHRH pulse generator by androgens. As observed by some authors in basal conditions and by others after endocrine manipulations. LH pulse amplitude seems also to be reduced in elderly men as compared to young subjects. This is most probably the consequence of a reduction in the amount of LHRH released by the hypothalamus. Indeed, challenge of the gonadotropes with low, close to physiological doses of LHRH in young and elderly men reveals no alterations in pituitary responsiveness when looking at either the response for immunoreactive LH or bioactive LH. Deconvolution analysis on data obtained after low-dose LHRH suggests a markedly prolonged plasma half-life of LH in elderly men, a finding which may explain the paradoxical increase of mean LH levels in face of the reduced or unchanged frequency and amplitude of LH pulses.

Obesity and cancer.

Large-scale studies have demonstrated that obesity increases the risk of developing some forms of cancer. The association between obesity and cancer may result from factors such as fat distribution or sex hormone levels. Studies have also shown a relationship between a high-fat, low-fiber diet and cancer risk. High estrogen levels and low progesterone levels are associated with an increased risk of endometrial cancer. Obesity is known to raise estrogen levels and may lower progesterone levels. Obesity may increase the risk of breast cancer, but the evidence is less clear, since factors, such as age, country of origin, body-fat distribution, and family history, also play a major role in determining breast cancer risk. Sex hormones, insulin, and nutritional factors are also involved in the etiology of breast cancer. The incidence of lung cancer is inversely related to body weight.