Clock genes alterations and endocrine disorders

Background

Various endocrine signals oscillate over the 24‐hour period and so does the responsiveness of target tissues. These daily oscillations do not occur solely in response to external stimuli but are also under the control of an intrinsic circadian clock.

Design

We searched the PubMed database to identify studies describing the associations of clock genes with endocrine diseases.

Results

Various human single nucleotide polymorphisms of brain and muscle ARNT‐like 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK) genes exhibited significant associations with type 2 diabetes mellitus. ARNTL2 gene expression and upregulation of BMAL1 and PER1 were associated with the development of type 1 diabetes mellitus. Thyroid hormones modulated PER2 expression in a tissue‐specific way, whereas BMAL1 regulated the expression of type 2 iodothyronine deiodinase in specific tissues. Adrenal gland and adrenal adenoma expressed PER1, PER2, CRY2, CLOCK and BMAL1 genes. Adrenal sensitivity to adrenocorticotrophin was also affected by circadian oscillations. A significant correlation between the expression of propio‐melanocorticotrophin and PER 2, as well as between prolactin and CLOCK, was found in corticotroph and lactosomatotroph cells, respectively, in the pituitary. Clock genes and especially BMAL1 showed an important role in fertility, whereas oestradiol and androgens exhibited tissue‐specific effects on clock gene expression. Metabolic disorders were also associated with circadian dysregulation according to studies in shift workers.

Conclusions

Clock genes are associated with various endocrine disorders through complex mechanisms. However, data on humans are scarce. Moreover, clock genes exhibit a tissue‐specific expression representing an additional level of regulation. Their specific role in endocrine disorders and their potential implications remain to be further clarified.     

The prevalence of obstructive sleep apnoea in women with polycystic ovary syndrome: a systematic review and meta-analysis

Sleep and Breathing - Obesity is a common risk factor for polycystic ovary syndrome (PCOS) and obstructive sleep apnoea (OSA). Both PCOS and OSA are associated with increased risk of type 2...     

Exercise decreases plasma total homocysteine in overweight young women with polycystic ovary syndrome

Women with polycystic ovary syndrome (PCOS) have a clustering of cardiovascular risk factors, such as obesity, lipid abnormalities, impaired glucose tolerance, insulin resistance, and hypertension. Exercise is reported to lower the incidence of cardiac events. The effect of exercise on plasma homocysteine concentrations, an independent cardiovascular risk factor, has not been previously reported in women with PCOS. We examined the effects of exercise on plasma total homocysteine concentrations in young overweight or obese PCOS women [age (mean +/- SD), 30.6 +/- 6.6 yr; body mass index, 35.49 +/- 7.57 kg/m(2)]. Twenty-one women consented to a 6-month exercise program; 12 women (exercisers) adhered to the program, whereas 9 (nonexercisers) did not. In both groups of women, the following parameters were recorded at baseline and 6 months: body mass index, waist-to-hip ratio, and aerobic capacity (maximal oxygen consumption); blood samples were taken after an overnight fast for plasma total homocysteine, insulin, and other biochemical parameters. A significant decrease in plasma total homocysteine concentrations (P < 0.001) and waist-to-hip ratio (P = 0.041) and a significant increase in maximal oxygen consumption (P = 0.019) were recorded at 6 months, compared with baseline in the exercise group. This decrease in homocysteine was not explained by changes in anthropometric or biochemical parameters. In contrast, no significant changes in any of the variables were observed in the nonexercise group. Our study has provided the first evidence that regular exercise significantly lowers plasma homocysteine in young overweight or obese women with PCOS, a group at increased risk of premature atherosclerosis. The precise mechanism by which exercise is associated with a reduction in homocysteine remains to be elucidated.     

Classical pituitary apoplexy: clinical features, management and outcome

OBJECTIVE: The term classical pituitary apoplexy describes a clinical syndrome characterized by sudden headache, vomiting, visual impairment and meningismus caused by the rapid enlargement of a pituitary adenoma usually due to haemorrhagic infarction of the tumour. Most published reports looking at the clinical features and management of pituitary apoplexy have not differentiated between patients with clinical and subclinical apoplexy, the latter diagnosed at surgery. Furthermore, little is reported on the clinical outcome, in particular visual and endocrinological, and the role of radiotherapy. The purpose of this study was to observe not only the clinical presentation but also the possible predisposing events, investigations, management, clinical outcome as well as the role of radiotherapy in patients presenting with classical pituitary apoplexy. PATIENTS AND DESIGN: In a retrospective analysis 1985-96, the medical records of 21 male and 14 female patients (mean age 49.8 years, range 30-74) with classical pituitary apoplexy were reviewed. This represents all patients seen with this condition over the stated period. MEASUREMENTS: In all patients, pre- and post- operative measurements were made of FT4, FT3, TSH, PRL, LH, FSH, cortisol (0900 h), GH, oestradiol (females) and testosterone (males). Pituitary imaging was by computerized tomography (CT) scan, magnetic resonance imaging (MRI) or both. RESULTS: Patients were followed for up to 11 years (mean 6.3 years: range 0.5-11). Headache (97%) was the commonest presenting symptom, followed by nausea (80%) and a reduction of visual fields (71%). Hypertension, defined as a systolic > 160 mmHg and/or a diastolic > 90 mmHg, was seen in 26% of patients. MRI correctly identified pituitary haemorrhage in 88% (n = 7), but CT scanning identified haemorrhage in only 21% (n = 6). By immunostaining criteria, null-cell adenomas were the most common tumour type (61%). Transsphenoidal surgery resulted in improvement in visual acuity in 86%. Complete restoration of visual acuity occurred in all patients operated on within 8 days but only in 46% of patients operated on after this time (9-34 days). Long-term steroid or thyroid hormone replacement was necessary in 58% and 45% of patients, respectively. Of the male patients, 43% required testosterone replacement, and long-term desmopressin therapy was required in 6%. Only two patients (6%) with tumour recurrence after transsphenoidal surgery for the initial apoplectic event, subsequently required radiotherapy. CONCLUSIONS: In classical pituitary apoplexy, headache is the commonest presenting symptom and hypertension may be an important predisposing factor. MRI is the imaging method of choice. Transsphenoidal surgery is safe and effective. It is indicated if there are associated abnormalities of visual acuity or visual fields because, when performed within 8 days, it resulted in significantly greater improvement in visual acuity and fields than if surgery was performed after this time. Radiotherapy is not indicated immediately as the risk of tumour recurrence is small, but careful follow-up initially with annual imaging is indicated in this group.     

Insulin and Metformin Regulate Circulating and Adipose Tissue Chemerin

OBJECTIVE

To assess chemerin levels and regulation in sera and adipose tissue from women with polycystic ovary syndrome (PCOS) and matched control subjects.

RESEARCH DESIGN AND METHODS

Real-time RT-PCR and Western blotting were used to assess mRNA and protein expression of chemerin. Serum chemerin was measured by enzyme-linked immunosorbent assay. We investigated the in vivo effects of insulin on serum chemerin levels via a prolonged insulin-glucose infusion. Ex vivo effects of insulin, metformin, and steroid hormones on adipose tissue chemerin protein production and secretion into conditioned media were assessed by Western blotting and enzyme-linked immunosorbent assay, respectively.

RESULTS

Serum chemerin, subcutaneous, and omental adipose tissue chemerin were significantly higher in women with PCOS (n = 14; P < 0.05, P < 0.01). Hyperinsulinemic induction in human subjects significantly increased serum chemerin levels (n = 6; P < 0.05, P < 0.01). In adipose tissue explants, insulin significantly increased (n = 6; P < 0.05, P < 0.01) whereas metformin significantly decreased (n = 6; P < 0.05, P < 0.01) chemerin protein production and secretion into conditioned media, respectively. After 6 months of metformin treatment, there was a significant decrease in serum chemerin (n = 21; P < 0.01). Importantly, changes in homeostasis model assessment–insulin resistance were predictive of changes in serum chemerin (P = 0.046).

CONCLUSIONS

Serum and adipose tissue chemerin levels are increased in women with PCOS and are upregulated by insulin. Metformin treatment decreases serum chemerin in these women.Polycystic ovary syndrome (PCOS), a common endocrinopathy affecting 5–10% of women in the reproductive age, is characterized by menstrual dysfunction and hyperandrogenism and is associated with insulin resistance and pancreatic β-cell dysfunction, impaired glucose tolerance (IGT), type 2 diabetes, dyslipidemia, and visceral obesity (1,2). The consequent hyperinsulinemia is more prevalent in lean and obese women with PCOS when compared with age- and weight-matched normal women (3).The metabolic syndrome is associated with excessive accumulation of central body fat. As well as its role in energy storage, adipose tissue produces several hormones and cytokines termed ‘adipokines’ that have widespread effects on carbohydrate and lipid metabolism. They appear to play an important role in the pathogenesis of insulin resistance, diabetes, and atherosclerosis (4). Furthermore, it is apparent that accumulation of visceral adipose tissue poses a greater cardiometabolic risk than subcutaneous adipose tissue (5) as removal of visceral rather than subcutaneous adipose tissue has been shown to improve insulin sensitivity (6). Moreover, differences in gene expression of adipocyte-secreted molecules (adipokines) suggest that there are inherent adipose tissue depot–specific differences in the endocrine function of adipose tissue. In relation to this, we have published data on the increased levels of vaspin in women with PCOS (7); vaspin is a recently described adipokine mainly formed in human visceral adipose tissue that has insulin-sensitizing effects (8).Recently, Bozaoglu et al. (9) reported chemerin as a novel adipokine, circulating levels of which significantly correlated with BMI, circulating triglycerides, and blood pressure, features of the metabolic syndrome. In addition, chemerin or chemerin receptor knockdown impaired differentiation of 3T3-L1 cells and attenuated the expression of adipocyte genes involved in glucose and lipid homeostasis (10).With the aforementioned in mind and the fact that there is no literature with regards to chemerin in human adipose tissue and its regulation, in study 1, we assessed circulating chemerin as well as mRNA expression and protein levels of chemerin in subcutaneous and omental adipose tissue depots in women with PCOS against age, BMI, and waist-to-hip ratio (WHR) in matched control subjects. Furthermore, we studied the in vivo (study 2) and ex vivo effects of insulin on circulating chemerin levels via a prolonged insulin-glucose infusion in humans and primary adipose tissue explant cultures, respectively. In study 3 we studied the effects of metformin therapy, widely used in the treatment of PCOS in women, on circulating chemerin levels in tandem with associated changes to clinical, hormonal, and metabolic parameters in the same cohort of PCOS in women. Additionally, we studied the ex vivo effects of metformin and steroid hormones in human primary adipose tissue explants.     

Cardiometabolic aspects of polycystic ovarian syndrome

It is estimated that 60%-7% of women of reproductive age have polycystic ovarian syndrome (PCOS). Women with this condition exhibit an adverse cardiovascular risk profile, characteristic of the cardiometabolic syndrome and given the high prevalence of PCOS in the female population, this condition may contribute towards the acceleration of cardiovascular disease among young women. This article summarizes the recent development and findings in the cardiometabolic abnormalities in patients with PCOS. Patients with PCOS have the clinical features of oligomenorrhoea, hirsutism and infertility; however, they also exhibit hyperinsulinemia, obesity, hypertension, dyslipidemia, and an increased pro-thrombotic state. They have an increased risk of type 2 diabetes and impaired glucose tolerance, and sleep apnea is also found more commonly in this population. However, despite the presence of cardiovascular risk factors and increased surrogate markers of cardiovascular disease it is unclear if they have accelerated atherosclerosis. End point studies are currently lacking and the available evidence are conflicting. Adipose tissue has emerged as an important endocrine organ over the last decade and gained recognition in having an important role in the cardiometabolic syndrome. Adiponectin that is secreted exclusively by adipocytes has recently been recognized as an important marker of cardiometabolic syndrome, obesity, type 2 diabetes, and coronary artery disease. Other adipocytokines like leptin and resistin have also recently been recognized. This article will address the current evidence for the adverse cardiovascular risk in PCOS and the other factors that may be implicated. Finally the therapeutic options for treatment will be discussed.     

Expression of orexin-A and functional orexin type 2 receptors in the human adult adrenals: implications for adrenal function and energy homeostasis

The hypothalamic peptides, orexin-A and orexin-B, have been implicated in the regulation of feeding behavior. In starved rats catabolic activity quickly predominates, reinforced by elevated corticosterone, independent of ACTH, implicating adrenal activity as a metabolic regulator. In view of these findings, we investigated whether orexin and orexin receptors are present in human adult adrenals and might therefore be implicated in hormonal regulation and energy homeostasis outside the central nervous system. RT-PCR, fluorescent in situ hybridization, immunoblotting, and immunostaining analysis confirmed the expression of the orexin type 2 receptor, but not of orexin type 1 receptor, in the adrenal cortex. Immunoblotting analysis also detected the presence of the prepro-orexin and its cleaved product orexin-A. Treatment of adult adrenal membranes with orexin-A increased the labeling of G(s), G(q), and, to a lesser degree, G(i), but not G(o). Stimulation with orexin-A induced cAMP and IP3 production in a dose-dependent manner. The data presented here provide conclusive evidence for the presence of orexin-A and orexin type 2 receptors in human adult adrenal glands. At the moment the functional relevance of this is uncertain. However, it is known that both orexin-A and orexin-B can induce corticosterone production in dispersed rat adrenocortical cells. Our data provide further evidence for a functional link between orexogenic signals and adrenal function. The concept that the peptide acting via these receptors in the adult adrenal is responsible for steroidogenesis and energy balance is attractive.