Summary • During aging, the secretory patterns of hormones produced by the hypothalamic-pituitary axis change. Likewise, glucose homeostasis tends to become imbalanced with age. • There is also a loss of bone and muscle mass and an increase in fat mass. • Other factors common in the elderly, such as chronic diseases, inflammation and malnutrition, can also affect the endocrine system. • Some of these changes are a useful adaptation, while hormonal intervention often causes significant adverse effects. • This work analyzes the effects of age on the hypothalamic-pituitary-adrenal axis, as well as changes in calcium and bone metabolism and glucose homeostasis. |
| Introduction |
Throughout adult life all physiological functions begin to gradually decline. Aging is characterized by changes in virtually all biological systems. Significant changes to the endocrine system result in healthy aging.
However, other factors, such as inflammation and caloric intake, also affect the aging process and are often associated with age-related chronic diseases.
This work reviews the response of the different components of the endocrine system to the aging process, including the response of the thyrotropic, somatotropic, adrenal and gonadal axes, as well as bone growth and calcium and glucose homeostasis.
| Hypothalamic-pituitary-peripheral organs axes |
> Thyrotropic axis
• Changes in thyroid function during aging
Several demographic studies, but not all, show that, after excluding people with thyroid disease and those with positive antithyroid antibodies, normal aging is accompanied by increased plasma concentrations of thyroid-stimulating hormone (TSH). . However, changes in TSH concentration appear to be dependent on regional iodine status .
Free thyroxine (FT4) concentrations remain stable with increasing age, although one study reported FT4 concentration increasing with age, while triiodothyronine (FT3) decreases over the life course.
The magnitude and characteristics of changes in thyroid function during aging are highly variable among individuals. Furthermore, with age, changes may occur in the bioactivity of TSH, making it less effective, or in the set point of the TSH receptor, making it less functional. Finally, the increased prevalence of thyroid autoimmunity and autonomic nodules with aging may alter thyroid hormone concentrations.
• Clinical relevance of changes in thyroid hormone concentrations during aging
Pooled data show that subclinical hyperthyroidism is associated with increased overall risk and related cardiovascular mortality, especially in the elderly and patients with comorbidities. However, a subsequent study showed that 85-year-olds with subclinical hyperthyroidism did not have a significantly lower 9-year survival than their euthyroid peers.
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Data from another meta-analysis, however, showed that people aged 65–79 years with TSH >10 mIU/l also have an increased risk of coronary heart disease, while this risk is not increased in those over 80 years of age. Therefore, the higher risk found in younger people appears to attenuate with age.
These data suggest that slightly reduced activity of the hypothalamic-pituitary-thyroid axis is beneficial during the aging process, a hypothesis also supported by a series of studies linking reduced thyroid hormone concentrations with decreased frailty.
Among older populations, lower FT4 concentrations were associated with greater physical function, while lower concentrations predicted future disability.
In conclusion , the aging process regulates the concentration of thyroid hormones. Although these alterations are highly variable, the thyroid hormone axis appears to decline with age, which is reflected by an increase in TSH concentration and a decrease in T3.
These changes are not a harmful aging process and may even be beneficial.
Therefore reference limits of hormone values are useful to avoid misclassification and overtreatment of the elderly, although these age-specific reference limits for thyroid function are not yet available.
> Somatotropic axis
The hypothalamic-pituitary-somatotropic axis is a hypothalamic-pituitary axis that includes the secretion of growth hormone (somatotropin) from the somatotropes of the pituitary gland into the circulation and the subsequent stimulation of insulin-like growth factor 1 (IGF-1). the English acronym).
Somatopause is the gradual and progressive decrease in normal hormonal secretion as the adult ages and is associated with an increase in adipose tissue.
It is mainly due to the reduced hypothalamic secretion of growth hormone-releasing hormone, which causes a decrease in the biosynthesis of the latter and its release by the anterior pituitary.
Although this decline in growth hormone–IGF-1 axis activity is considered to contribute to age-related changes, growth hormone–IGF-1 deficiency or resistance also results in prolonged life expectancy, for example. at least in animals.
From these data the question arises whether growth hormone deficiency constitutes a beneficial adaptation to aging and therefore does not need treatment.
In conclusion , aging and the so-called somatopause are accompanied by decreased concentrations of growth hormone and IGF-1, but no intervention has been effective to stop or reverse somatopause.
> Control of appetite and food consumption
Appetite and food consumption decline with normal aging, predisposing the elderly to malnutrition . This is common in those over 65 years of age and has been implicated in the progression of chronic diseases that usually affect them, in addition to increasing mortality.
Possible hormonal causes of anorexia of aging are increased activity of cholecystokinin, leptin and various cytokines and decreased activity of ghrelin. All of these changes appear to significantly decrease appetite. Future research will determine whether it is possible to correct these changes with pharmacological interventions.
> Adrenal axis
• Glucocorticoids
Aging of the hypothalamic-pituitary-adrenal axis is generally associated with increased late-day and evening cortisol concentrations , a peak in the early morning, lower circadian cortisol amplitudes, and more irregular cortisol secretion characteristics.
As with the other hypothalamic-pituitary axes, it is not clear whether these changes in cortisol secretion are due to age or whether they reflect other effects, such as the presence of mild inflammation, sleep disorders, or changes in blood pressure. social or emotional state associated with age.
Changes in the hypothalamic-pituitary-adrenal axis that occur during aging may have clinical consequences. Previous studies showed that more dynamic axis activity (i.e., greater diurnal decline) is related to better physical performance and cognitive function in older adults than less activity. Additionally, high to normal urinary free cortisol concentrations are associated with increased risk of Alzheimer’s disease.
Aging may also influence the availability of tissue cortisol, since the activity of 11-β hydroxysteroid dehydrogenase, which transforms inactive cortisone into active cortisol, decreases during aging. This increase in cortisol availability leads to increased local generation of glucocorticoids, which can cause adverse changes in the elderly. In muscle, for example, increased 11-β hydroxysteroid dehydrogenase activity is associated with lower muscle strength.
• Dehydroepiandrosterone and its sulfate
Adrenal secretion of the steroid precursor dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) also gradually decreases over time.
By the time a person reaches 70–80 years of age, DHEAS concentrations are about 20% of peak values in men and 30% of peak values in women, relative to people <40 years of age. DHEA and DHEAS are inactive precursors that are converted to androgens and estrogens in peripheral tissues. This source of androgens is important, since less than 50% of these hormones are of testicular origin.
- Higher concentrations of DHEA and DHEAS were associated with psychological well-being and better physical functioning, including muscle strength and bone density, and with anti-inflammatory and immunoregulatory actions.
- Lower concentrations of DHEAS were associated with increased risk of cardiovascular events and cardiovascular mortality in those over 50 years of age.
In conclusion , it remains to be known whether these alterations reflect or cause age-associated changes in functional capacity, cognition, and mood.
> Gonadal axis
• Aging of the female reproductive system
The aging of the female reproductive system and the hormonal changes that accompany it are produced by the accelerated depletion of the ovarian reserves of primordial follicles. The lower quality of oocytes in the remaining follicles contributes to the decrease in fertility after the fourth decade of life.
The decrease in the number of antral follicles sensitive to follicle-stimulating hormone (FSH), which is proportional to the reduced reserve of primordial follicles, is reflected in the decreasing concentrations of anti-Müllerian hormone secreted by the granulosa cells of the follicles (a marker of ovarian reserve produced in primary, secondary and early antral follicles) and inhibin B (a marker of ovarian activity).
The rapid reduction of ovarian reserve during reproductive life goes unnoticed due to the conservation of regular cycles, mostly ovulatory.
When the follicles become insufficient, the cycle becomes irregular (>7 days longer than previous cycles), which signals the early phase of the menopausal transition, at an average age of 46 years.
The longer cycle, the absence of some periods and the prolonged intervals of amenorrhea signal the passage to the late phase of the menopausal transition, which ends with the almost total exhaustion of the ovarian follicles and the last menstrual period (after 12 months of amenorrhea) around the age of 51 years.
As the menopausal transition progresses, cycles are more often anovulatory . Conversely, in ovulatory cycles, the duration of the luteal phase and hormone concentrations remain stable throughout reproductive life and the menopausal transition, with the exception of progesterone values, which decrease slowly.
Changes in gonadotropin secretion through the transition and after menopause, characterized by increases in luteinizing hormone (LH) and FSH pulse width and loss of preovulatory waves of gonadotropin, are caused by alteration of the feedback produced by intrinsically determined ovarian decline, of sex steroids and the production of inhibin A and inhibin B.
Throughout reproductive life and the menopausal transition there is a tendency to decrease the adrenal production of DHEA and DHEAS and the mixed adrenal and ovarian production of testosterone and androstenedione. However, LH-stimulated thecal cells in postmenopausal ovaries still contribute to circulating testosterone concentrations for up to 10 years.
The multi-organ clinical consequences of the hormonal changes produced during the menopausal transition and after menopause, such as alterations in vasomotor regulation, bone metabolism or the urogenital system, are mainly produced by changes in estrogen production.
In this regard, the concentration of late postmenopausal estrogens originating from the aromatization of androgens in peripheral tissues, although usually low relative to their concentration during the reproductive period, is still clinically significant, as illustrated by its association with clinical situations. such as bone fractures and breast cancer and by the appearance of vasomotor and joint symptoms and the increased risk of fractures during pharmacological inhibition of aromatase in postmenopausal women.
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• Aging of the male reproductive system
Men do not experience an equivalent of menopause, as many of them retain their sex hormone production and fertility into old age. However, aging affects the male reproductive system.
Testicular volume in men over 75 years of age decreases by 30% and the number of Sertoli cells is reduced, as reflected by the modest increase in FSH concentrations. Changes in sperm quality are limited to a modest decrease in ejaculate volume and sperm with suboptimal motility and morphology.
In healthy men aged 25 - 75 years, 25% of morning plasma testosterone values slowly and progressively decrease. Additionally, sex hormone binding globulin (SHBG) levels increase about 1% per year. This causes the concentration of non-SHBG-bound testosterone, especially the 2% biologically active free testosterone, to decline more rapidly than total testosterone (about 50%) at these ages.
The concentration of free and total testosterone varies between people, although approximately 20% of men > 65 years of age have testosterone values below normal for young people and this proportion increases with age.
Other male hormones also decline with age, including total and free dihydrotestosterone and the precursor to plasma testosterone, androstenedione (produced in the testes and adrenals). Excretion of the urinary metabolite androstanediol glucuronide is also decreased.
Plasma levels of estradiol, produced by the aromatization of testosterone and androstenedione in peripheral tissues such as fat and striated muscles, do not decrease with age.
The inadequate increase in LH values in response to the reduction of free and total testosterone in many elderly people reveals other changes in gonadotropin secretion, characterized by a decrease in the frequency of higher amplitude LH pulses, presumably produced by the reduced hypothalamic secretion of gonadotropin-releasing hormone.
The independent increase in hepatic production of SHBG is another factor, possibly a consequence of the decrease in the activity of the somatotropic axis. Obesity is a confounding factor, since a BMI of 25–29 kg/m2 is associated with lower values of SHBG and total plasma testosterone than when weight is normal and with BMI ≥30 kg/m2 the values of total and free testosterone decrease as a result of additional hypothalamic dysfunction.
| The relative contribution of aging and concomitant diseases, clinical or subclinical, to changes in reproductive hormones in older adults continues to be the subject of discussion. Low testosterone in the elderly is a marker of poor health and has been linked to increased of the risk of death. Sexual dysfunction is associated with low plasma testosterone values. |
The cut-off values for the appearance of symptoms, such as decreased libido and erectile dysfunction, are located at the lower limit of normality for young men—total testosterone < 320 ng/dl (11 nmol/l), and free testosterone < 6.4 ng/dl (0.22 nmol/l).
The importance of testosterone as a precursor to estradiol, which has important physiological effects in men, for example on bone homeostasis, is increasingly recognized.
The benefits of testosterone treatment on muscle, bone, sexual function, and well-being are limited to the elderly who initially had low testosterone values. However, these benefits are modest and long-term data on important topics, such as effects on the prostate and cardiovascular system, are scarce.
| Calcium and bone homeostasis |
Older age is an important risk factor for bone mass and strength, as it causes an increased risk of falls and fractures.
Osteoporosis is caused by an imbalance between osteoblasts that form bone and osteoclasts that resorb bone. These processes are influenced by osteocytes, which are housed inside the mineralized bone and function as sensors of mechanical load.
Estrogen deficiency at menopause and the loss of estrogens and androgens in older adults are considered the main endocrine factors contributing to osteoporosis . Increasing evidence, especially from studies in rodents, suggests that fundamental intracellular processes in bone, such as increased oxidative stress, cellular aging, inflammation, osteocyte apoptosis, DNA damage, and several others, are also important in the production of osteoporosis and Fragility fractures with aging.
These intrinsic age-related mechanisms are accompanied by changes in endocrine systems and increased incidence of endocrine diseases with age, including type 2 diabetes.
• Sex steroids
Estrogens and androgens are important for the growth and maintenance of tissue mass and the function of bones and muscles. Its actions on bone occur mainly by binding of ligands to sex steroid receptors, including estrogen receptor α and β and the androgen receptor. The imbalance between bone formation and resorption in estrogen deficiency affects trabecular bone, with loss of connectivity, and cortical bone, with thinning and cortical porosity.
Increased osteocyte apoptosis after loss of ovarian or testicular function is mainly due to increased oxidative stress. Furthermore, hypogonadism is associated with increased formation of glycation end products and inflammation and thus contributes to the intrinsic causes of osteoporosis that occur with aging.
- In women, the possible role of changes in progesterone, androgen, inhibins, and FSH levels in increasing the effects of estrogen deficiency on bone loss during the perimenopausal period remains to be defined.
- In elderly men , estrogen is the dominant sex steroid that regulates bone resorption, and both estrogen and testosterone are important in maintaining bone formation. Sex steroids are also considered important in the changes in calcium and phosphate homeostasis that occur with aging.
Postmenopausal women have higher plasma phosphate values than men of the same age, and some studies found higher plasma calcium values in elderly women than in elderly men, suggesting sexual dimorphism in calcium and phosphate homeostasis in postmenopause and a possible association with sex hormone concentrations. Estrogen induces renal phosphate loss and hypophosphatemia, reduces renal calcium excretion, and increases intestinal calcium absorption.
• Glucocorticoids
Osteoporosis and fractures are important side effects of glucocorticoid use or excess and are caused by the effects of glucocorticoids on bone and muscle strength. The generation of systemic and locally produced corticosteroids and the sensitivity of bone cells to glucocorticoids increase with age.
Glucocorticoids are strong inhibitors of bone formation that function, at least in part, by stimulating apoptosis of osteoblasts and osteocytes and suppressing the generation of new osteoblasts through attenuation of Wnt signals.
They also increase bone resorption by promoting osteoclast survival. All of these effects may contribute to age-related declines in bone mineral density, cortical porosity, bone strength, and increased fractures.
• Vitamin D, parathyroid hormone, fibroblast growth factor 23 and Klotho
Vitamin D and its metabolites and parathyroid hormone control whole-body calcium and phosphate homeostasis.
Plasma vitamin D values decrease with age, which may lead to lower intestinal calcium absorption and the development of secondary hyperparathyroidism.
Circulating parathyroid hormone values also appear to increase with age, independently of 25-hydroxyvitamin D, ionized calcium, phosphate, and renal function.
- Primary hyperparathyroidism , a disease more common in postmenopausal women, is a well-known cause of decreased bone mineral density and fractures.
- Secondary hyperparathyroidism can also increase the risk of fractures, as can the decline in kidney function that occurs with aging.
Fibroblast growth factor 23 ( FGF23) is a hormone secreted by osteocytes in bone, which together with its cofactor α-Klotho inhibits phosphate reabsorption and the production of 1,25-hydroxyvitamin D in the kidney.
FGF23 begins to increase during the early stages of chronic renal failure in response to decreased phosphate excretion, but other age-related changes in this skeletal–renal endocrine system have not been studied.
• Growth hormone and IGF-1
Growth hormone and its mediator, IGF-1 , are the major determinants of peak bone mass. The decline in hormone and IGF-1 concentrations during aging is associated with bone loss. Between 20 and 60 years of age, the IGF-1 content in bones declines by 60%. The decline in the bone matrix of these proteins along with protein-3 is associated with reduced bone density and risk of hip fractures.
| Hormone replacement treatment reduced women’s risk of fractures, but was associated with increased breast cancer and cardiovascular disease, according to the large Women’s Health Initiative study . This produced a sharp reduction in the use of hormone replacement. |
In men, there are no studies with the administration of hormones or testosterone that allow evaluating the rate of fractures.
| Glucose homeostasis |
Glucose homeostasis depends on a balance between its ingestion, use and production and is closely controlled by insulin . This balance is altered with aging. From the fourth decade of life, blood glucose begins to increase. Alteration of cerebral glucose metabolism could precede histological findings in Alzheimer’s disease and probably worsens it.
Reduced insulin pulsatility and decreased action
Insulin is secreted in a pulsatile manner with two types of pulses: high-frequency pulses with 6-minute intervals and ultradian pulses with 90-minute intervals. Pulsatile insulin secretion is abnormal (deficient and chaotic) in type 2 diabetes. However, these alterations can also be observed in non-diabetic elderly people.
The liver is exposed to pulses of insulin from the islets directly through the portal vein. Insulin is degraded during the first passage, slowing the amplitude of the pulses when they reach the peripheral tissues. Insulin is less effective in suppressing hepatic glucose production when it reaches the liver in a disordered manner than when it arrives normally.
This mechanism is altered in aging due to disordered delivery of insulin to the liver. In addition, during aging there is an increase in insulin clearance in the liver.
• Effect of age on glucose elimination
The disposal of glucose throughout the life cycle continues to be a topic of debate. Normally most of the glucose, in a glucose loading test, is eliminated by the muscles. In aging this glucose delivery is reduced and appears to be independent of insulin.
The decrease in insulin would be related to a certain degree of obesity and the alteration of the fat/lean muscle mass ratio.
Other influencing factors are the magnitude of caloric intake, less physical activity, medications and diseases. However, exercise does not modify the age-related changes that occur in beta cells.
• Diabetes in elderly people
After age 85, alterations in glucose metabolism reach a plateau and even decline. In the elderly, beta cell dysfunction plays a greater role in diabetes than in younger subjects. About 25% of people > 65 years of age are diabetic and this is only detected with the 2-hour glucose tolerance test, but the HbA1c test is preferable to detect diabetes and detection increases considerably if the HbA1c test is added. fasting blood sugar.
It is generally accepted that in elderly people and taking into account the increase in life expectancy, diabetes should be screened and if prediabetes is detected, lifestyle changes adapted to the patient will be indicated to prevent diabetes and its micro and macrovascular complications. .
| Conclusions |
- During aging, changes occur in various endocrine systems, including alterations in hormonal secretion.
- The magnitude of these changes varies considerably between individuals and reference values of hormone concentrations must be established in elderly people.
- It is difficult to differentiate whether these changes are due to aging or if they are related to other processes such as chronic diseases, inflammation, nutritional status, etc.
- There is limited information on the effects that these changes can produce on physical function, well-being, morbidity and ultimately mortality. Future studies are required to clarify these aspects.
