Cognition, mood and fatigue in patients in the early stage of multiple sclerosis

QUESTION UNDER STUDY: Cognitive impairment occurs during multiple sclerosis (MS) and contributes to the burden of the disease, but its effect in the initial phase of MS still needs to be better understood. METHODS: We prospectively studied 127 early MS patients presenting with a clinically isolated syndrome (CIS) or definite MS, a mean disease duration of 2.6 years, and with minor disability (mean Expanded Disability Status Scale score 1.8). Patients were tested for long-term memory, executive functions, attention, fatigue, mood disorders, functional handicap and quality of life (QoL). Twenty-one CIS patients were excluded from study as the diagnosis of MS could not be confirmed. RESULTS: Over the 106 MS patients analysed, 31 (29.3%) were cognitively impaired (23.6% for memory, 10.4% for attention and 5.7% for executive functions). Cognitive deficits were already present in CIS patients in whom the diagnosis was not yet confirmed (20%). Impaired cognition was associated with anxiety (p = 0.05), depression(p = 0.004), fatigue (p = 0.03), handicap (p <0.001) and a lower QoL (p <0.001). After adjustment for QoL, handicap, depression, anxiety and fatigue were no longer associated with the presence of cognitive deficits. CONCLUSIONS: In this well-defined early MS group one third of the patients already exhibited cognitive deficits, which were usually apparent in an effortful learning situation and were generally mild. Mood disorders, fatigue, handicap and decreased QoL were all associated with the occurrence of cognitive deficits. QoL itself appeared to take all the other factors into account. Our results confirm the existence of an interplay between cognitive, affective and functional changes and fatigue in early MS.     

Changes in whole body concentrations of cortisol, thyroid hormones, and sex steroids during early development of the chum salmon, Oncorhynchus keta.

Significant amounts of cortisol (20 ng/g) and thyroid hormones thyroxine (T4, 20 ng/g) and triiodothyronine (T3, 10 ng/g), as well as estradiol (8 ng/g) and testosterone (4 ng/g), are present in fertilized eggs of chum salmon. Changes in the concentrations of these hormones in the developing embryo and larvae were monitored until after the emergence of the fry from the gravel bed. Cortisol concentrations in the developing embryo fell steadily from 20 ng/g at fertilization to 2.5 ng/g after 3 weeks, increased slightly to 10 ng/g by 1 week before hatching, and maintained this level during the early stages of yolk sac absorption. During the later stages of yolk sac absorption, cortisol concentrations increased markedly and remained at about 30 ng/g until emergence, when they declined to 10-15 ng/g. In contrast, both T4 and T3 levels were stable during early development, decreased gradually during yolk sac absorption, and increased slightly during emergence. Estradiol and testosterone profiles were similar to that of cortisol during early development. Testosterone levels remained low throughout emergence. Likewise, estradiol levels were low during yolk sac absorption but showed a transient increase at the time of emergence. These hormonal changes are discussed in the context of egg development and subsequent downstream migration.     

Free fatty acids do not influence the concentrations of free steroid hormones in serum under physiological conditions

In several recent studies it has been suggested that FFA may influence the concentrations of unbound steroid hormones in serum, but the experimental design of these studies has been questioned. We have reexamined the effects of oleic acid on the unbound concentrations of several steroid hormones in serum, including cortisol, testosterone, and estradiol. The results demonstrate that under physiological conditions, oleic acid does not affect the unbound concentrations of these hormones when assays are carried out with whole serum.     

Relationship of sex hormones to bone geometric properties and mineral density in early pubertal girls

This study aimed to evaluate the associations among serum 17beta-estradiol (E2), testosterone (T), sex hormone-binding globulin (SHBG), bone geometric properties, and mineral density in 248 healthy girls between the ages of 10 and 13 yr old. The left tibial shaft was measured by peripheral quantitative computed tomography (Stratec XCT-2000; Stratec Medizintechnik, GmbH, Pforzheim, Germany). The cortical bone and marrow cavity areas were expressed as proportions of the total tibial cross-sectional area (CSA). Cortical thickness and total volumetric bone mineral density (vBMD) were also determined. These tibial geometric and densitometric measures were correlated against the serum sex hormone concentrations after controlling for age and body size. The results showed that E2 was negatively associated with marrow cavity proportion (r = -0.19, P = 0.003) and positively associated with cortical proportion and thickness and with total vBMD (r = 0.26, P < 0.001; r = 0.25, P < 0.001; and r = 0.23, P < 0.001, respectively). However, T was not associated with these bone variables. On the other hand, SHBG was positively associated with marrow cavity proportion (r = 0.17, P = 0.007) and negatively associated with cortical proportion and thickness and with total vBMD (r = -0.14, P = 0.029; r = -0.16, P = 0.010; and r = -0.18, P = 0.005, respectively). Total bone CSA did not correlate with E2, T, or SHBG. These results suggest that E2 has a positive effect on bone geometric and densitometric development by suppressing bone turnover at the endocortical surface during the early pubertal period, that SHBG plays an opposite role to E2, and that T has no detectable effect.     

Inhibition of thyrotrophin-releasing hormone responsiveness by physiological concentrations of thyroid hormones in the cultured rat pituitary gland.

Diced quarter anterior pituitaries from mature females Wistar rats were cultured in synthetic medium with or without added serum. Using each culture as its own control, the thyrotrophin-releasing hormone (TRH) dose-thyrotrophin (TSH) response characteristics of both media were similar; significant TSH secretion being stimulated at TRH doses around 1-5 X 10(-9) mol/l. During days 1-3 of culture, basal TSH secretion fell significantly but TRH responsiveness was unchanged. Neither tri-iodothyronine (T3) nor thyroxine (T4) influenced basal TSH secretion. In both culture media inhibition of TRH responsiveness was demonstrated with concentrations of T3 and T4 within the ranges 1-5 X 10(-12) to 1-5 X 10(-9) mol/l for T3 and 6-5 X 10(-10) to 6-5 X 10(-7) mol/l for T4. Equivalent inhibition was accompanied by similar T3 concentrations whether T3 or T4 supplements were used, suggesting that T4 itself has no feedback action. The similar concentrations of T3 required to inhibit TRH responsiveness in media either with or without serum suggest that the pituitary is responsive not only to free but also to total thyroid hormone concentrations, since serum-free medium contains no thyroid hormone-binding protein.     

Endogenous levels of dehydroepiandrosterone sulfate, but not other sex hormones, are associated with depressed mood in older women: the Rancho Bernardo Study.

OBJECTIVE: The purpose of this study was to determine whether endogenous steroid hormone levels are associated with depressed mood in community-dwelling older women. DESIGN: A cross-sectional population-based study. SETTING: Rancho Bernardo, California PARTICIPANTS: A total of 699 non-estrogen using, community-dwelling, postmenopausal women (aged 50 to 90 years) from the Rancho Bernardo cohort who were screened for depressed mood and had plasma obtained for steroid hormone assays in 1984-1987. MEASUREMENTS: Plasma levels of total and bioavailable (non-SHBG-bound) estradiol and testosterone, estrone, androstenedione, cortisol, dehydroepiandrosterone, and (DHEA) and its sulfate (DHEAS) were measured by radioimmunoassay. Mood and depression were assessed using the Beck Depression Inventory. RESULTS: Only DHEAS levels were significantly and inversely associated with depressed mood, and the association was independent of age, physical activity, and weight change (P = .0002). Age, sedentary lifestyle, and weight loss were positively associated with depressed mood. Alcohol intake, cigarette smoking, marital status, type of menopause, and season of testing were unassociated with depressed mood. A subset of 31 women with categorically defined depression had lower DHEAS levels compared with 93 age-matched nondepressed women (1.17 +/- 1.08 vs 1.57 +/- .98 micromol/L; P = .01). CONCLUSIONS: These results add to the evidence that DHEA/S is a neuroactive steroid and point to the need for careful long-term clinical trials of DHEA therapy in older women with depressed mood.     

Female sex hormones, salt, and blood pressure regulation

There are gender-associated differences in blood pressure (BP) in humans, with men having higher BP than age-matched pre-menopausal women and being at greater risk for cardiovascular and renal diseases. The mechanisms responsible for the gender differences in BP control and regulation are not clear, although there is some evidence that interactions between sex hormones and the kidneys could play a role. However, the response to salt in pre- and post-menopausal women, and in particular the influence of exogenous and endogenous female sex hormones on renal hemodynamics and tubular segmental sodium handling, have been poorly investigated. Recently we have shown that both endogenous and exogenous female sex hormones markedly influence the systemic and renal hemodynamic response to salt. We have found that BP in young normotensive women, regardless of oral contraceptive use, is rather insensitive to salt. However, the renal hemodynamic and the tubular responses to salt vary significantly during the normal menstrual cycle and with the administration of oral contraceptives. Furthermore, after the menopause, BP tends to become salt sensitive, a pattern that could be due to aging as well as to the modification of the sex hormone profile. These observations provide new insights pertaining to potential mechanisms explaining the lower incidence of cardiovascular disease and progression of renal disease in pre-menopausal women (which tend to disappear with the menopause); these observations also emphasize the importance of considering more carefully the phase of the menstrual cycle whenever conducting physiologic studies in women and enrolling women in clinical studies. Finally, increased salt sensitivity in menopausal women strongly encourages the use of diuretics.     

Depression and sex hormones in elderly women

We aimed to study the relation between sex hormones and depression among elderly women. The study was carried out on 74 volunteered female subjects above 60 years of age. Each subject was asked to fulfill the geriatric depression scale (GDS) questionnaire and further evaluated for clinical depression by a psychiatrist using the DSM IV diagnostic criteria. For statistical analysis, subjects were later divided in two groups, according to the presence of clinical depression. Cognitive functions were assessed with the standardized mini mental test (SMMT). Disability in the activities of daily living was assessed with instrumental activities of daily living (IADL) scale. Plasma levels of estrogen, testosterone, progesterone, and dehydroepiandrosterone sulfate (DHEA-S) were measured with chemiluminescent methods, and plasma levels of androstenedione were measured with radioimmunoassay. Among 74 subjects, 34 (39%) had clinical depression. Age, number of years spent in education, SMMT scores, and IADL scores did not differ between the depressive and non-depressive groups. Plasma sex hormone levels were not found to be different between the two groups.     

Age, sex and late relapse in childhood lymphoblastic leukaemia

Of 53 children with lymphoblastic leukaemia in their first remission who reached the fourth year after stopping treatment, 4 have subsequently relapsed and their cases are described. All are boys and 3 were over 10 at diagnosis despite there being only 6 such patients in the group overall. This suggests that teenage males are at special risk of late relapse and should not be considered cured on criteria applicable to younger females.     

Age, sex, and serum thyrotropin concentrations in primary hypothyroidism

We studied the relationship between age, sex, serum thyroxine concentrations, and serum thyrotropin concentrations in 202 patients with primary hypothyroidism whose ages ranged from 10 to 89 years. The results from two groups of patients were analysed, both combined and separately, by multiple linear regression analysis of the factors age, sex, group, and serum free T4 index or serum T4 concentration, to predict serum TSH. The serum free T4 index or T4 values and age were negatively correlated with the serum TSH concentrations (p less than 0.001) for all comparisons. In contrast, there was no significant relationship between sex and serum TSH concentrations in these hypothyroid patients. The age-related decline in serum TSH concentrations in hypothyroidism was apparent during adolescence and early adult life (ages 10 to 39 years) and in elderly subjects (ages 61 to 89 years). We conclude that age is a determinant of TSH secretion independent of the level of thyroid secretion.     

Locust adipokinetic hormones: carrier-independent transport and differential inactivation at physiological concentrations during rest and flight.

Since concomitant release of structurally related peptide hormones with apparently similar functions seems to be a general concept in endocrinology, we have studied the dynamics of the lifetime of the three known adipokinetic hormones (AKHs) of the migratory locust, which control flight-directed mobilization of carbohydrate and lipid from fat body stores. Although the structure of the first member of the AKHs has been known for 20 years, until now, reliable data on their inactivation and removal from the hemolymph are lacking, because measurement requires AKHs with high specific radioactivity. Employing tritiated AKHs with high specific radioactivity, obtained by catalytic reduction with tritium gas of the dehydroLeu2 analogues of the AKHs synthesized by the solid-phase procedure, studies with physiological doses of as low as 1.0 pmol per locust could be conducted. The AKHs appear to be transported in the hemolymph in their free forms and not associated with a carrier protein, despite their strong hydrophobicity. Application of AKHs in their free form in in vivo and in vitro studies therefore now has been justified. We have studied the degradation of the three AKHs during rest and flight. The first cleavage step by an endopeptidase is crucial, since the resulting degradation products lack any adipokinetic activity. Half-lives for AKH-I, -II and -III were 51, 40, and 5 min, respectively, for rest conditions and 35, 37, and 3 min, respectively, during flight. The rapid and differential degradation of structurally related hormones leads to changes in the ratio in which they are released and therefore will have important consequences for concerted hormone action at the level of the target organ or organs, suggesting that each of the known AKHs may play its own biological role in the overall syndrome of insect flight.