BMH Medical Journal - Muraleedharan

BMH Med. J. 2020; 7(Suppl): Early Online. Geriatrics & Gerontology Initiative: International Workshop on Care of the Elderly

Changes occurring in the human body is programmed from womb to tomb at the time of conception. Changes in every body systems follow this programme. Changes related with aging cannot be prevented, but can be modified. It is also noted that there is individual differences in the aging process and it is not decided by chronologic age alone. This is due to many factors like genetic, environmental and lifestyle. With daily functioning, there is constant damage in every cells. This is less important in cells which do not replicate in postnatal life. Processes like DNA repair partly overcome this cellular damage but the repair process lag behind damage as the age advances. In case of cells which replicate rapidly like intestinal epithelium and blood cells, this may be relevant. Repeated multiplications cause DNA damage and mitogenicity and reflected in the length of telomeres of the chromosomes with advancing age.

Changes in biorhythms

Physiologic rhythms are characteristic of hormone secretions and is noted with LH, GH, TSH, ACTH and melatonin. Changes are noted in Day/Night and light dark distribution of secretory pulses, frequency and amplitude. These secretory pulses are driven by the pacemaker situated in suprachiasmatic nucleus by feedback regulation. Defect in the feedback may be responsible for the changes noted with advancing age. This cause variability in functions like heart rate, blood pressure, EEG, auditory response and response to stress are decreased in old age but less affected in physically trained individuals. These changes impair adaptation of the individual to stress.

Physiological reserves decrease with advancing age making individual susceptible to disease. This is observed in many functions like cardiac output, glomerular filtration, pulmonary functions and hormonal reserves.

When the reserve decreases, even a mild disturbances put heavy demands on corrective mechanisms resulting in illness, hospitalisation and death. When scoring systems in ICU like APACHE IV are used, age is an important determinant of outcome like death or discharge from the hospital. Responses like delirium occur in diverse illnesses like urinary or chest infection, myocardial infarction and GI haemorrhage showing common response to diverse illness.

Endocrine system shares many of the factors which are associated with aging.

Elder population is increasing globally. In the 100 years from 1950 to 2050, number of persons above 80 (Projected figure) will increase from 14.5 million to 395 million. Even though the number of years of life expectancy has increased since 2000 AD, there is no proportionate increase in the healthy life maintaining physical, mental and social independence. This causes years of life with physical restriction and morbidity. This can be reduced to an extent by measures like cessation of smoking, keeping BMI in the healthy range and adequate physical activity from younger age.

Hence, a person with healthy lifestyle lives longer with more number of healthy, active and independent years without frailty.

From middle of adult life, there is decline in protein synthesis, immune function, muscle mass and strength and bone mineral content with increase in fat mass. These changes cause loss of muscle strength, impaired mobility and loss of balance causing falls and decreased physical endurance. This situation is referred to as frailty causing fall and fractures, difficulty for activities of daily living with dependence on others.

Loss of muscle power occur due to loss of muscle mass, defect in innervation and damage to surrounding joints. Chronic systemic illness also contribute to this and further amplified by sedentary lifestyle and disuse.

Many of the disabilities associated with aging has a link with endocrine system. These changes are either coincidence or bear a cause and effect relationship. Even after a number of years of research in this area, there is no consensus regarding the plan of action in many areas.

Diabetes and carbohydrate intolerance

40 to 50% aged 65 years and above has carbohydrate intolerance or diabetes. The intensity can be reduced with diet and exercise, supported with drugs.

Hypothalamic pituitary thyroid axis

Abnormalities in thyroid function is seen in the elderly. T4 in the lower limit of normal with modest increase in TSH is seen. This is often due to autoimmune destruction of thyroid and not part of aging. However, normal T4, elevated TSH and low T3 seen in the elderly denote age related thyroid dysfunction independent of autoimmunity. This is due to decrease in peripheral mono deiodination of T4 to T3. It is prudent to take age specific TSH norms when treating persons above 70 years because the elevated levels are often interpreted as subclinical hypothyroidism. Benefits of treatment of subclinical hypothyroidism in the aged is disputed. However, subclinical hyperthyroidism has to be treated for preventing atrial fibrillation, ischemic heart disease, osteoporosis and fracture and for prevention of dementia.

Hypothalamic pituitary adrenal axis

Age alter mean hormone levels, secretion and elimination rates, pulse amplitude and number, loss of pattern of pulses and circadian periodicity. Late day and evening rise of cortisol, earning morning cortisol (Phase advance), lower circadian amplitude are features of old age. Peak morning cortisol occur at 6.30 am unlike 9 am in the young. Higher evening level of cortisol cause abnormalities like decrease in GH, GHRH and IGF 1 levels, lower LH, GnRH, Testosterone and estrogen values, decrease in neurogenesis and immune function with increase in abdominal visceral adiposity, blood pressure and blood glucose due to insulin resistance. Outcome of these changes include osteopenia, sarcopenia, syndrome X, cognitive decline and immune compromise and manifest as fall, fractures, cardiovascular disease, memory loss and infections. Changes in timing, amplitude and frequency of HPA axis and cortisol is poorly understood and at present, beyond the scope of intervention. The reasons for these changes are not clear. Fall in DHEA and its sulphate in old age (Andropause) is due to decreased functional capacity of zona reticularis. Cortisol levels are maintained. Even though value of DHEA in old age is only one third of youth, benefit of DHEA replacement is not proved.

GH Axis and aging

GH secretion in the normal occur in pulses and more of the pulses with higher amplitude occur at night at stage 3 and 4 of NREM sleep. Major factors controlling GH secretion are GHRH (Growth Hormone Releasing Hormone) and GHRIH (Growth Hormone Release Inhibiting Hormone – Somatostatin) both secreted by hypothalamus and Ghrelin from the fundus of the stomach. It is noted that there is close correlation between Ghrelin pulses and GH pulses in health. Orally administered Ghrelin analog MK-677 is found to increase GH levels in volunteers. Both amplitude and frequency of pulses decrease with advancing age. This is referred to as somatopause. Parallel to this is decrease in muscle mass (Sarcopenia) and loss of muscle strength. Hence, use of GH and or Ghrelin analogs offer therapeutic potential in the aged with frailty. However, their long term use is associated with side effects like increased incidence of cancers, glucose intolerance and diabetes, hypertension and cardiovascular events. Less significant side effects like arthralgia, carpel tunnel syndrome, edema and gynecomastia also may occur with GH therapy. Because of this, routine use of GH or ghrelin analogs are not recommended.

Reproductive aging in men, unlike in women, changes are slow, subtle and not clearly defined. Androgens in men include testosterone, dihydrotestosterone, androsterone, androstane diol, DHEA and its sulphate. Most of the testosterone is derived from testes. 80% of Dihydrotestosterone is produced in the periphery from testosterone by enzyme 5 alpha reductase. Androstenedione, DHEA and DHEAS are produced in the adrenal. Testosterone levels peak in the second and third decade and thereafter decline at a rate of 1 to 1.5% annually. Parallel to this, there is increase in Sex Hormone Binding Globulin (SHBG) at 1% per year. Combinedly, these two factors cause steep fall in testosterone action in the elderly. However, male hypogonadism is not defined purely on the levels of testosterone and elevated LH but needs symptoms and signs of androgen deficiency. Aging is associated with loss of Leydig cells and Sertoli cells and testes volume of 80 years is only 30% of 30 year old. Diagnosis of late onset Hypogonadism should be made after showing low testosterone levels on multiple occasions along with symptoms of androgen deficiency. Routine screening is not recommended. Low testosterone cause low appendicular muscle strength, slow walking and frailty. Cognition is impaired. Loss of bone mass, fractures and cardiometabolic dysfunctions are other sequalae.
Lack of clear cut clinical features and laboratory values cause difficulty and delay of diagnosing declining gonadal function in men. It also make decision making of replacement therapy difficult. Many of the symptoms like lethargy, reduced concentration, sleep disturbances, irritability and mood changes are nonspecific and could happen with other physical illness. There are no authentic randomised trials supporting benefits of androgen replacement. End points of treatment and duration of therapy is not known. The situation is quite different in the younger age where the symptoms like sweating, hot flushes, insomnia , libido, sexual dysfunction and mood changes are rapidly reversed by testosterone replacement. Muscle strength, bone mass and body composition like fat mass and lean body mass are also benefitted.

Testosterone replacement using 6 mg patches over three years with placebo control showed decrease in fat and increase in lean body mass but no change in muscle strength or bone mineral density. However, there is small increase in libido, erectile power and satisfaction in the testosterone group compared to placebo. The present recommendation is to start testosterone therapy for those elderly men who are symptomatic and have testosterone levels low with gonadotropin and PRL values appropriate to levels of testosterone. The issue should be discussed with the patient and the benefits and risk explained. There is no consensus regarding duration of testosterone therapy.

Reproductive aging in women

Women enter menopause around the age of 50 with low levels of female sex steroids. It is noted that the protective benefits of endogenous estrogen on menstruating women is lost with menopause. There is increase in coronary events and is not reversed by hormone replacement therapy with estrogen alone (In women with absent uterus) and 0estsrogen progestin treatment in those with uterus. However, HRT in women below 50yrs of age protect them from coronary artery disease. (Danish report). Even though lipoprotein profile of these women is normal, there is drop in CV events after HRT.

Menopause is defined as permanent cessation of menstruation for 12 months and is a retrospective diagnosis. Both gametogenic function (Follicles) and hormonal function (Theca cells) decline. Index of follicular function is Anti Mullarian Hormone (AMH) which decline when follicular number is exhausted. Clinical signs include   sweating, hot flushes, mood changes (vasomotor), urogenital complaints like pruritus, dyspareunia, atrophic vaginitis, dysuria and postmenopausal osteoporosis with increased fracture risk. Smoking makes menopause to occur even earlier.

Postmenopausal hormone replacement therapy rapidly relieve acute menopausal symptoms with recurrence on stoppage. Long term use of HRT is controversial. Earlier, many studies favoured their role to prevent coronary disease and bone loss. However, Women’s Health Initiative (WHI), a multicentre study involving 40 US centres during 1993-98 showed there is no benefit and it could even cause adverse effects like breast cancer. The trial consisted of Estrogen, estrogen and progestin and placebo. However, it was thought that this may be because of delay in starting of HRT in the above study as atherosclerotic changes which are already established cannot be reversed. Hence HRT can be recommended for a period of 5 years in early menopause or in the perimenopausal period. Minimum duration of treatment should be more than 6 years and HRT may not be beneficial for those with established atherosclerotic plaque. HRT benefits are noted for osteoporotic fractures. However breast cancer incidence increased in oestrogen users. To an extent, deleterious effects of HRT is overcome by use of Selective Estrogen Receptor Modulators (SERMs). SERMS like raloxifene and tamoxifene reduce incidence of breast cancer and prevent osteoporosis. In elderly women, there is decrease in the levels of testosterone responsible for decrease sexual function. Testosterone patches used for one year is found to improve sexual function in these women. However, there is no consensus regarding the harmful side effects of androgens in postmenopausal women.

Because of indefiniteness in the outcome, HRT is not advocated as a general measure but can be used in selected persons. The present policy is to use other cardioprotective measures, treatment of diabetes, hypertension and high cholesterol and use of aspirin for antiplatelet benefits and use of bisphosphonates for bone loss.

Osteoporosis in old age and treatment

Osteoporosis is a common accompaniment of old age. There is decrease in bone mass and strength which predispose to fall and fractures. It occurs in both sexes, abruptly in women after menopause and slowly after 50 in men. The diagnosis is established with DEXA scan which show T score below -2.5. Prevention of osteoporosis should start in the very young as peak bone mass is achieved around 25 years after which there is only bone loss. In healthy persons, the loss is steady but augmented by lack of exercise, sedentary habits, smoking, alcohol and drugs likely to cause bone loss. Pharmacologic agents used include estrogens (for prevention), Raloxifene (SERM) calcitonin, bisphosphonates, denosumab and teriparatide.

Estrogens are useful in early menopause and in the early perimenopausal period to prevent bone loss. Raloxifene is useful for prevention of vertebral fracture with little effect on hip and nonvertebral fracture. Bisphosphonate prevent resorption by altering the function of osteoclasts inducing apoptosis. Denosumab is a monoclonal antibody directed against Receptor Activator of Nuclear factor Kappa b ligand (RANK Ligand) preventing osteoclast differentiation. Teriparatide, a PTH analog alters bone cycle favoring bone formation over resorption.
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Equally important are nonpharmacologic intervention. Elderly are at disadvantage because of poor vision and hearing, loss of muscle power and loss of balance. Measures aimed at addressing these issues can help them to prevent fracture. This include cataract surgery, better lighting, stopping psychotropic drugs, more exercise and vitamin D supplements. Proper footwear is also important.

Overall emphasis for overcoming age related bone loss and its consequences are nonpharmacological and drugs are used only when strongly indicated

Frailty

As the age advance, loss of muscle mass and physical dependence occur which is referred to as frailty . In addition, there is psychosocial form of frailty also. Cardiovascular Health Model (CHS) propose simple questionnaire to` assess frailty (FRAIL) and SARC-F model for sarcopenia.

FRAIL score

SARC-F Score

Strength – difficulty in lifting/carrying 10 lb
Assistance for walking
Rise from chair
Climb stairs
Fall >2

Endocrine diseases share many of the aspects of frailty. The symptoms are often nonspecific and slow in onset that they are often missed. Very often, the frailty in old age is caused by an endocrine disease which is missed. These include hypothyroidism, subclinical hyperthyroidism, addisons, pituitary failure and diabetes mellitus. Identification and treatment of these is rewarding.

Sleep and aging

Hormones are not secreted in a steady fashion. Fluctuations in secretions occur even normally under basal condition. Variation of hormones occur with cycles of 60 to 120 mins. This is called ultradian variation while fluctuation over the day and night is called circadian rhythm. Fluctuations lasting more than 24hrs is called infradian changes, classic example for this is menstrual cycles. 24 hour pattern of hormone secretion is dictated by two mechanisms – the sleep wake cycle and day night changes decided by the hypothalamic pacemaker situated in the arcuate nucleus. As age advances, altering the architecture of sleep with sleep fragmentation occur. Nocturnal wake time increases. This is associated with normal night sleep and day time sleep.

Age and water homeostasis

Changes in water homeostasis is observed with advancing age. Multiple factors are responsible for this. These include changes in body composition, alteration of renal function and changes noted in the sensitivity of thirst center and ability of supraoptic and paraventricular nucleus secretion of arginine vasopressin. These changes are usually mild and of no clinical significance. However, in some persons, hyper and hypo osmolality, hypo and hypernatremia and hyper and hypovolemia occur. Commonest cause of hyponatremia is Syndrome of Inappropriate Secretion of ADH (SIADH) and often no cause could be found out. Hyponatremia in elderly cause neurocognitive dysfunction, gait instability and falls, loss of bone mass and fractures, hospitalization and long term of institutional care. As symptoms of these abnormality is often subtle, high index of suspicion is needed for diagnosis which often involve laboratory investigations. It can be noted that serum sodium, blood volume and osmolality are often related. Of the three factors, body water is the determining factor for serum Na and osmolality. Frequency of hyponatremia depend on the cutoff point used for diagnosis. With a cutoff point of 135mEq/L the frequency is 15 to 22% while with cutoff point of 130mEq, it is 1 to 4%. Most common cause of hyponatremia in elderly is SIADH and very often, it is idiopathic. However, many conditions like stress, lung diseases, malignancies, nervous system injuries and pain are associated with SIADH. Hyponatremia in elderly predict high mortality and morbidity like falls, fractures and bone loss. There is also cognitive impairment in this group.

Summary

With advancing age, there are a number of changes occurring in the body including the endocrine system. These physiological changes should be understood and attempt should be made to delay or prevent these changes by lifestyle measures. Drugs should be used as the last resort and not the first step as there is no endpoint regarding dose or duration of therapy and it also cause many side effects with which may be harmful.

References

1. Harrisons text book of Internal Medicine

2. Williams Text book of endocrinology, 14th Edn

3. Endocrine and metabolic clinic of North America June 2013

4. Journal of Clinical endocrinology and metabolism – Multiple references

Endocrinology Of Aging