© Borgis - Postępy Nauk Medycznych 7/2015, s. 451-457
Marta Jonas1, Alina Kuryłowicz1, 2, *Monika Puzianowska-Kuźnicka1, 3
Starzenie i układ endokrynny
Aging and the endocrine system
1Department of Human Epigenetics, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warszawa
Head of Department: prof. Puzianowska-Kuznicka, MD, PhD
2Department of Internal Medicine and Endocrinology, Medical University of Warsaw
Head of Department: prof. Tomasz Bednarczuk, MD, PhD
3Department of Geriatrics and Gerontology, Medical Centre of Postgraduate Education, Warszawa
Acting Head of Department: Jacek Putz, MD, PhD
Starzenie charakteryzuje się stopniowym pogarszaniem funkcji wszystkich tkanek i narządów. Wskutek starzenia znacząco zmieniają się rytm i sekwencja wydzielania oraz ilość większości hormonów produkowanych przez podwzgórze, przysadkę oraz obwodowe komórki i narządy endokrynne. Na przykład, znamiennemu zmniejszeniu ulega wydzielanie melatoniny, hormonu wzrostu, hormonów płciowych, dehydroepiandrosteronu oraz licznych innych hormonów, podczas gdy wydzielanie TSH i kortyzolu może się z wiekiem zwiększyć, również u osób, które starzeją się pomyślnie (bez chorób). To z kolei zwykle pogarsza niekorzystne skutki starzenia. Niektóre związane ze starzeniem zmiany hormonalne mogą jednak odgrywać rolę ochronną, np. niska (prawidłowa) lub nieznacznie obniżona aktywność osi przysadkowo-tarczycowej u osób starszych wydaje się być powiązana z dłuższym przeżyciem i lepszym stanem zdrowia.
Co istotne, ponieważ u osób starszych objawy mogą być nietypowe i do siebie podobne mimo różnej etiologii, niekiedy trudno jest odróżnić skutki starzenia jako takiego od skutków spowodowanych występowaniem chorób.
Biological aging is characterized by the progressive deterioration of the function of all tissues and organs. As a consequence of aging, rhythm, sequence, and amount of majority of the hormones secreted by the hypothalamus, pituitary, as well as by the peripheral endocrine cells and organs significantly change. For example, the secretion of melatonin, growth hormone, sex hormones, dehydroepiandrosterone and of other numerous hormones decreases, while the secretion of TSH and cortisol may increase in aging individuals, including these who age successfully (without disease). This in turn results in worsening of the adverse effects of aging. Some aging-related hormonal changes however might play a protective role in aging; for example, low-normal or slightly decreased activity of the pituitary-thyroid axis in the elderly seems to be associated with longer survival and better health.
Notably, since in the elderly signs and symptoms can be atypical and similar regardless of their etiology, it is sometimes difficult to distinguish the effects of aging per se from these caused by diseases.
Biological aging is characterized by the progressive deterioration of the function of all fissues and organs, leading to the loss of ability to restore homeostasis under stressful conditions and, consequently, to the increased risk of development of aging-related diseases. This phenomenon also affects the neuroendocrine function of hypothalamus-pituitary axis, as well as influences the structure and function of peripheral endocrine organs. Aging is also accompanied by changes in the number and sensitivity of receptors that may change the responsiveness of target tissues to hormones and neurotransmitters. However, it is sometimes difficult to distinguish the effects of aging per se on endocrine physiology from these caused by diseases since their signs and symptoms might overlap. In addition, signs and symptoms of endocrine disorders in the elderly can be poorly expressed and atypical (1). In this review we present basic concepts regarding pathophysiology of some endocrine dysfunctions in elderly patients, as well as brief guidelines regarding diagnosis and treatment of these conditions.
In the second decade of life nocturnal peak of melatonin secretion starts to decline, and in the eighth decade of life it is usually less than a quarter of this observed in young adults; moreover, in some individuals peak secretion might be completely absent. This phenomenon may reflect the progressive, aging-related calcification of the pineal gland causing loss of secretory tissue; however, there is no direct relationship between the extent of gland calcification and hormone secretion (2). Loss of nocturnal secretory pulse most possibly contributes to the high prevalence of disturbances of the circadian rhythm and other physiological rhythms. Melatonin supplementation is therefore considered an efficient treatment for individuals with serious age-related sleep disturbances; it is usually inefficient however in patients with mild sleep problems. A starting dose for most elderly adults is as low as 0.3 mg taken 1 hour before or at bedtime. If after a week of treatment situation does not change, the dose should be doubled or increased further; in some patients the effective daily dose can be as high as 5 mg. Alternatively, the patient can take a second dose if he/she is still not asleep 10-15 minutes after waking up at night (3). The data regarding the use of melatonin as a treatment in elderly patients with cognitive impairment associated with dementia are not consistent; nevertheless, in some patients suffering from Alzheimer’s disease, administration of melatonin may reduce hyperactivity in the evening and at night (4).
Aging is accompanied by a gradual impairment of growth hormone (GH) secretion and a parallel decrease in serum levels of insulin-like growth factor-1 (IGF-1); daily GH secretion in old individuals might be only 5-10% of its secretion in young adults. This is a consequence of the aging-associated decrease in hypothalamic GH-releasing hormone (GHRH) baseline secretion and subsequent decrease of pituitary responsiveness to GHRH, as well as of age-related changes in somatotrope secretory function, and of the lifestyle (lower physical activity and sleep disturbances) (5).
The clinical picture of „physiological”, aging-associated GH deficiency includes the decrease of lean body mass and bone mineral density and the increase of adipose tissue mass (especially within abdominal cavity), all leading to the increased rate of metabolic disturbances, cardiovascular disease, fractures, and mortality. Encouraging results of GH replacement therapy in children suffering from GH axis insufficiency lend support to the concept of its use in the elderly to combat aging-related changes in body composition, muscle strength, bone mineral density, as well as to increase the quality of life. Indeed, it was shown in randomized trials, that the recombinant human GH (rhGH) replacement therapy in the elderly resulted in the increase in lean body mass and in quality of life; however, such beneficial effect was accompanied by a number of significant side effects such as glucose intolerance or diabetes, edema, carpal tunnel syndrome and arthralgias. In addition, genetic and functional studies performed in animal models, as well as association studies in humans, strongly suggest that lower activity of the IGF-1 axis is associated with longer life, while IGF-1 excess might promote neogenesis (6). Therefore, nowadays the rhGH treatment is recommended only for patients with GH deficiency that is not associated with aging, and should not be used as an element of anti-aging treatment, unless aging is accompanied by diseases such as sarcopenia, in which the administration of GH can provide therapeutic benefits (7).
Aging per se is not associated with a significant change in the size of the thyroid, but the density of this gland increases. The uptake of iodine remains unchanged or slightly decreases. Healthy aging is characterized by the increase of thyroid stimulating hormone (TSH) secretion and serum concentration, a slight decrease of triiodothyronine (T3) and free T3 (fT3) concentrations and an increase of reverse T3 (rT3) levels. Thyroxin (T4) synthesis also decreases with age; however, since its half-life time in circulation is increased, the levels of T4 and free T4 (fT4) remain unchanged. The lowest activity of the thyroid hormone axis was observed in centenarians, which is consistent with numerous data indicating that low-normal or subclinical thyroid insufficiency in elderly and long-lived individuals is associated with a longer survival and with a better health (8).
The percentage of individuals with anti-thyroperoxidase and anti-thyroglobulin antibodies significantly increases with age until the ninth decade of life and decreases thereafter. Aging is also associated with the increasing incidence of thyroid diseases. Notably, their clinical manifestations are less pronounced compared to younger individuals and the symptoms are frequently incorrectly attributed to aging. Elderly patients are often treated with drugs that disrupt the function of the thyroid axis. Therefore, in case of biochemical abnormalities but without clear symptoms, blood analysis should be repeated, and patient’s health status and treatment should be reviewed (9).
It is estimated that after the age of 60, subclinical hypothyroidism may affect up to 20% of women and up to 8% men (it should be remembered though, as mentioned above, that it might be only a sign of natural thyroid aging), while clinically overt symptoms: fatigue, cognitive impairment, depression and metabolic complications, are present only in approximately 5% of elderly individuals. Overt hypothyroidism or subclinical hypothyroidism with TSH levels > 10 μIU/ml should be treated according to the generally accepted protocols, initially with 12.5 μg of levothyroxine per day, a dose that can be doubled after 2 weeks and further increased every 2-4 weeks until the target TSH level is achieved. This varies depending on age: for individuals under the age of 70 years, the recommended TSH concentration is 2.5-3.5 μIU/ml, while for those over 70 years – 4-5 μIU/ml. Treatment of elderly individuals with subclinical hypothyroidism and TSH level below 10 μIU/ml is a subject to individual decision. Since epidemiological studies have not confirmed its association with cognitive impairment, depression, or increased overall mortality, it is suggested that in individuals free of hypothyroidism symptoms and in relatively good health, hormone supplementation is not necessary but the patient should be monitored so as not to miss the appearance of the symptoms indicating the need for treatment (10).
Both subclinical and overt hyperthyroidism are also more common in the elderly, affecting up to 6% and to 0.5-3% of the population over 60 years, respectively; however, the diagnosis is less apparent due to lack of the characteristic hypermetabolic symptoms which are usually replaced by fatigue, muscle weakness, atrial arrhythmias, weight loss, or accelerated bone loss. It was shown in most epidemiological studies that both subclinical and overt hyperthyroidism may lead to the increased risk of total and cardiovascular mortality in patients over 65 years old and, therefore, should be treated in each case. The etiology of hyperthyroidism in the elderly does not differ significantly compared to younger individuals and is usually associated with Graves’ disease (GD). On the other hand, toxic adenoma, toxic multinodular goiter and iodine-induced hyperthyroidism (after administration of contrast agents or iodine-rich drugs such as amiodarone) are more common in the elderly than in young patients. The diagnostics of hyperthyroidism in the elderly is the same as in younger age groups, but the treatment might be slightly different. In elderly patients with GD there is a good chance of achieving remission with prolonged (up to 24 months) pharmacological treatment. The initial dose of methimazole should not exceed 30 mg/day (notably, due to its hepatotoxicity, propylthiouracil is not routinely recommended for treatment of hyperthyroidism). In patients with thyroid autonomy, surgery and radioiodine administration are the most effective treatment options. In these patients, methimazole is often used to treat hyperthyroidism before implementation of radical therapy and one should remember that it does not induce permanent remission and discontinuation leads to relapse of the disease. However, in elderly patients with increased surgical risk and/or inability to comply with radiation safety guidelines, long-term treatment with thionamides is an option to consider (11).
The prevalence of thyroid nodules and of all types of thyroid neoplasms increases with age. Although both papillary and follicular thyroid carcinomas are more common in women, the female-to-male ratio declines in the elderly and males are at higher risk of more aggressive forms of thyroid cancer. In older patients, sporadic medullary thyroid carcinoma is also more frequent. Age is a strong negative predictor in prognosis of the anaplastic (undifferentiated) thyroid carcinoma, and by the time of diagnosis most patients have widespread local invasion and distant metastases. The diagnosis and treatment of thyroid cancers in the elderly are typical and the only difference is the rate of TSH suppression after radical treatment: in the elderly suppression can be less strict (12).
VITAMIN D AND PARATHORMONE
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