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An animal model of postmenopausal bone loss can be defined as a living animal in which spontaneous or induced bone loss due to ovarian hormone deficiency can be studied, and in which the characteristics of the bone loss and its sequalae resemble those found in postmenopausal women in one or more respects. Although in comparison to humans, the skeletal mass of rats remains stable for a protracted period during their lifespan, rats can be ovariectomized to make them sex-hormone deficient, and to stimulate the accelerated loss of bone that occurs in women following menopause. Ovariectomy induced bone loss in the rat and postmenopausal bone loss share many similar characteristics. These include: increased rate of bone turnover with resorption exceeding formation; and initial rapid phase of bone loss followed by a much slower phase; greater loss of cancellous than cortical bone; decreased intestinal absorption of calcium; some protection against bone loss by obesity; and similar skeletal response to therapy with estrogen, tamoxifen, bisphosphonates, parathyroid hormone, calcitonin and exercise. These wide-ranging similarities are strong evidence that the ovariectomized rat bone loss model is suitable for studying problems that are relevant to postmenopausal bone loss.
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PMID:The ovariectomized rat model of postmenopausal bone loss. 177 31

Obesity results from a greater consumption of energy than is used by the body. As this energy is stored, fat cells enlarge, producing the characteristic pathology of obesity. The pathologic enlargement of fat cells, in turn, produces altered levels of many peptide and nutrient signals that are responsible for the disease we call "obesity." The genetic makeup of human beings, which reflects a long history of relative scarcity of foodstuffs, has run into an age of surfeit, and many people cannot readily adapt. Thus, the increased intake of food does not signal satiety, and there is a gradual increase in energy stores as intake of energy outpaces need as we grow older. Against this background of struggle between nature and nurture, it is possible to identify an increasing number of defects or etiologies that produce obesity. For most patients, however, it is not possible to connect obesity to a specific cause. Leptin deficiency and defects in the leptin receptor both produce human obesity. Defects in the pro-opiomelanocortin receptor system, the peroxisome proliferator-activated receptor-gamma, the agouti-related peptide, and a few other rare genetic syndromes are also associated with human obesity. Of the genetic causes, Prader-Willi syndrome is the most common. Hypothalamic injury following craniopharyngioma is the most common neuroendocrine cause. Endocrine disorders such as Cushing's disease, polycystic ovary disease, and growth-hormone deficiency can lead to increased body fat. In the modern world, exposure to a high-fat diet predisposes many people to obesity, and this problem is compounded by the low levels of activity now required for daily living. Treatment strategies must be developed against this background.
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PMID:Etiology and pathogenesis of obesity. 1069 81

Central hypothyroidism (CH) is a rare cause of hypothyroidism, generally due to either pituitary or hypothalamic defects. On the basis of its etiology, it is possible to distinguish acquired and hereditary forms. Hereditary CH can be isolated or associated with combined pituitary hormone deficiency (CPHD). In the former case, alterations of only two genes, TSHbeta and the TRH receptor, have so far been described as responsible for the disorder. In hereditary CH associated with CPHD, inactivating mutations of different pituitary transcription factors (HESX1, PROP-1, POU1F1) have been found involved in the pathogenesis of the disease. Finally, an association between CH and severe obesity has been described in patients with leptin receptor (Leptin-R) mutations. The clinical consequences of CH in adult life vary greatly depending on the etiology, the severity of the thyroid impairment, the extent of the associated hormone deficiencies, and the age of the patient at the time of the onset of the disease. In general, acquired CH is less severe than the congenital form because of the constitutive activity of the wild-type TSH-receptor. Symptoms and signs of thyroid insufficiency are usually milder than those of primary hypothyroidism, and goiter is always absent. In CPHD, most patients have other endocrine manifestations of the disease (growth failure, delayed puberty, adrenal insufficiency, diabetes insipidus) that lead them to seek medical attention before the hypothyroidism becomes severe. Early diagnosis of the congenital form by neonatal screening for hypothyroidism is strongly recommended in order to avoid cretinism. Replacement therapy with L-thyroxine administration has to be established as soon as possible.
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PMID:Central hypothyroidism: consequences in adult life. 1196 21

One of the major concerns of perimenopausal women is obesity-and for a good reason. Both general and abdominal obesity as well as loss of skeletal muscle (sarcopenia) are accelerated through the menopausal transition and lifestyle changes as well as sex hormone deficiency play important roles. Most well conducted clinical trials have demonstrated hormone replacement therapy induced reversal or at least impairment of menopausal changes in body composition and the common worry that it causes weight gain is unsubstantiated. Coaching of weight loss in obese individuals is often a frustrating task but is nevertheless of immense importance because of the health hazards of obesity. Through the climacteric period, short-term hormone replacement therapy, with or without androgens for preservation of muscle mass, might inhibit obesity and this is likely to boost motivation for introduction of more comprehensive and long-lasting initiatives linked to persistent weight loss and long-term health benefit.
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PMID:Changes in body composition at menopause--age, lifestyle or hormone deficiency? 1280 21

Cushing's disease is uncommon in childhood. It is usually caused by the oversecretion of adrenocorticotrophic hormone (ACTH) by a pituitary corticotroph adenoma. Clinical abnormality is often undetected for long periods of time. The principal clinical features are growth retardation and obesity. We present four patients who were diagnosed with Cushing's disease in a tertiary hospital from January 1995 to December 2002. There were two boys and two girls, aged 10-15 years. The main clinical features at presentation were growth failure and excessive weight gain. The interval between onset of symptoms and diagnosis ranged from 2.5 to 5 years. All patients presented moon face and increased fat around the neck. In all patients, 24-hour urinary free cortisol was high and loss of normal serum cortisol circadian rhythm (3/3) and suppression of cortisol to less than 50 % of the basal level with high-dose but not with low-dose dexamethasone (2/2) were observed. Pituitary microadenoma was detected by magnetic resonance imaging in three patients; no tumor was detected in the fourth patient and inferior petrosal sinus sampling was performed, showing left lateralization of ACTH central secretion. Therapy consisted of transsphenoidal surgery in all patients. Two patients are in remission, one patient presented disease recurrence requiring total hypophysectomy because the tumor could not be completely removed and one patient had persistent disease after a second intervention and required pituitary radiotherapy. Two patients showed pituitary hormone deficiency after therapy.
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PMID:[Diagnosis, treatment and long-term outcome in Cushing's disease]. 1288 47

Obesity and multiple pituitary hormone deficiency are common complications after surgery for childhood craniopharyngioma. We hypothesized that post craniopharyngioma surgery, children are at high risk for the metabolic syndrome, including insulin resistance due to excess weight gain and GH deficiency. This study characterized body composition (anthropometry and dual energy x-ray absorptiometry) and metabolic outcomes in 15 children (10 males and 5 females; age, 12.2 yr; range, 7.2-18.5 yr) after surgical removal of craniopharyngioma. In 9 subjects, outcomes were compared with those of healthy age-, sex-, body mass index-, and pubertal stage-matched controls. Insulin sensitivity was measured by 40-min iv glucose tolerance test. Seventy-three percent of subjects were overweight or obese. Sixty-six percent had normal growth velocity without GH treatment. Subjects had increased abdominal adiposity (P = 0.008) compared with controls. However, there was no significant difference in total body fat. Subjects had higher fasting triglycerides (P = 0.02) and lower high density lipoprotein cholesterol to total cholesterol ratio (P = 0.015). Insulin sensitivity was equally reduced for subjects and controls (P = 0.86). After craniopharyngioma removal, patients had more features of the metabolic syndrome compared with controls. This could be a result of hypothalamic damage causing obesity and GH deficiency. Further studies exploring predictors of the metabolic syndrome after craniopharyngioma surgery are required.
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PMID:Features of the metabolic syndrome after childhood craniopharyngioma. 1471 31

Present knowledge on the effects of growth hormone (GH) and insulin-like growth factor-I (IGF-I) deficiency on aging and lifespan are controversial. Studying untreated patients with either isolated GH deficiency due to GH gene deletion, patients with multiple pituitary hormone deficiency due to PROP-1 gene mutation and patients with isolated IGF-I deficiency due to deletions or mutations of the GH receptor gene (Laron syndrome); it was found, that these patients despite signs of early aging (wrinkled skin, obesity, insulin resistance and osteopenia) have a long life span reaching ages of 80-90 years. Animal models of genetic GH deficiencies such as Snell mice (Pit-1 gene mutations) the Ames mice (PROP-1 gene mutation) and the Laron mice (GH receptor gene knock-out) have a statistically significant higher longevity compared to normal controls. On the contrary, mice transgenic for GH and acromegalic patients secreting high amounts of GH have premature death. Those data raise the question whether pharmacological GH administration to adults is deleterious, in contrast to policies advocating such therapies.
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PMID:Do deficiencies in growth hormone and insulin-like growth factor-1 (IGF-1) shorten or prolong longevity? 1562 Dec 11

In the human body, the productions, levels and cell receptors of most hormones progressively decline with age, gradually putting the body into various states of endocrine deficiency. The circadian cycles of these hormones also change, sometimes profoundly, with time. In aging individuals, the well-balanced endocrine system can fall into a chaotic condition with losses, phase-advancements, phase delays, unpredictable irregularities of nycthemeral hormone cycles, in particular in very old or sick individuals. The desynchronization makes hormone activities peak at the wrong times and become inefficient, and in certain cases health threatening. The occurrence of multiple hormone deficits and spilling through desynchronization may constitute the major causes of human senescence, and they are treatable causes. Several arguments can be put forward to support the view that senescence is mainly a multiple hormone deficiency syndrome: First, many if not most of the signs, symptoms and diseases (including cardiovascular diseases, cancer, obesity, diabetes, osteoporosis, dementia) of senescence are similar to physical consequences of hormone deficiencies and may be caused by hormone deficiencies. Second, most of the presumed causes of senescence such as excessive free radical formation, glycation, cross-linking of proteins, imbalanced apoptosis system, accumulation of waste products, failure of repair systems, deficient immune system, may be caused or favored by hormone deficiencies. Even genetic causes such as limits to cell proliferation (such as the Hayflick limit of cell division), poor gene polymorphisms, premature telomere shortening and activation of possible genetic "dead programs" may have links with hormone deficiencies, being either the consequence, the cause, or the major favoring factor of hormone deficiencies. Third, well-dosed and -balanced hormone supplements may slow down or stop the progression of signs, symptoms, or diseases of senescence and may often reverse or even cure them. If hormone deficiencies and imbalances are the major causes of senescence, what then is the treatment? Crucial for the treatment of senescent persons is to make a correct diagnosis by making up an anamnesis of all symptoms related to hormone disturbances, conducting a thorough physical examination, and getting laboratory tests done such as serum and 24-hour urine analyses. The physician should look not only for hormone deficiencies, including the mildest ones, but also for any alterations in hormone circadian cycles, and for the presence of any factors--nutritional, dietary, behavioral, lifestyle, environmental (including illumination and indoor, outdoor, or dietary pollutants)--that cause or aggravate hormone deficiencies. After completion of the detailed diagnostic phase and obtaining and analyzing the results of the tests, treatment can start. In general, before supplying hormones, all other factors that contribute to senescence should be eliminated. After that, supplements of the missing hormones can then be administered, carefully respecting an appropriate timing of their intake, and eventually recommending measures such as lifestyle changes to restore circadian rhythmicity.
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PMID:The "multiple hormone deficiency" theory of aging: is human senescence caused mainly by multiple hormone deficiencies? 1639 12

Leptin has emerged over the past decade as a key hormone in not only the regulation of food intake and energy expenditure but also in the regulation of neuroendocrine and immune function as well as the modulation of glucose and fat metabolism as shown by numerous observational and interventional studies in humans with (complete) congenital or relative leptin deficiency. These results have led to proof-of-concept studies that have investigated the effect of leptin administration in subjects with complete (congenital) leptin deficiency caused by mutations in the leptin gene as well as in humans with relative leptin deficiency, including states of lipoatrophy or negative energy balance and neuroendocrine dysfunction, as for instance seen with hypothalamic amenorrhea in states of exercise-induced weight loss. In those conditions, most neuroendocrine, metabolic, or immune disturbances can be restored by leptin administration. Leptin replacement therapy is thus a promising approach in several disease states, including congenital complete leptin deficiency, states of energy deprivation, including anorexia nervosa or milder forms of hypothalamic amenorrhea, as well as syndromes of insulin resistance seen in conditions such as congenital or acquired lipodystrophy. In contrast, states of energy excess such as garden-variety obesity are associated with hyperleptinemia that reflects either leptin tolerance or leptin resistance. For those conditions, development of leptin sensitizers is currently a focus of pharmaceutical research. This article summarizes our current understanding of leptin's role in human physiology and its potential role as a novel therapeutic option in human disease states associated with a new hormone deficiency, ie, leptin deficiency.
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PMID:Leptin in humans: lessons from translational research. 1917 40

Craniopharyngioma is a rare, benign, suprasellar brain tumor associated with a significant number of endocrine and metabolic impairments. Growth hormone deficiency, caused by the tumor itself or by its subsequent surgical treatment, is the most common hormone deficiency in these patients and replacement is frequently necessary. Hypothalamic obesity observed after surgery treatment, whether combined with radiotherapy or not, presents with increased abdominal fat and altered lipid profiles and is likely caused by both disruption of the mechanisms controlling satiety, hunger and energy balance and impairment of sensitivity to leptin, insulin and ghrelin axis. It is well known that hyperlipemia is associated with acute pancreatitis, both as a precipitant and as an epiphenomenon. Moreover, the increased incidence of acute pancreatitis during growth hormone therapy is possibly due to increased enzyme production (e.g., amylase, lipase and elastase). We report the case of a 13-year-old girl affected by craniopharyngioma on growth hormone replacement treatment who developed acute pancreatitis. We suggest including routine evaluation of lipid profile during follow-up of all children on growth hormone treatment, especially those affected by hypopituitarism secondary to craniopharyngioma, given pancreatic adverse effects of growth hormone replacement therapy and associated metabolic impairment due to hypothalamic obesity.
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PMID:Acute pancreatitis in a girl with panhypopituitarism due to craniopharyngioma on growth hormone treatment. A combination of risk factors. 1950 96


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