Endocrinology and Aging

The world is getting older

In the developed world, people >80 y/o are the fastest growing subset

In the US, people over 60 will increase from 35 million (12.4%) to 71.6 million (19.6%) by 2030

Worldwide, lifespan expected to increase another 10 years by 2050

Therefore need to focus on healthy aging

Aging Process

As people get older, parts don’t work as well In the endocrine system, there is a decrease

in feedback and feed-forward systems Organs become less responsive to stimuli,

and hormones are not released at the same levels

Thyroid Axis

Changes with Aging

Decreased pituitary responsivenessLess TSH response to TRHLess rise in TSH to low T4/T3

Thyroid does not respond to TSH as wellLess T4 response to TSH surge

Decreased peripheral conversion of T4 to T3 due to decreased 5’ deiodinase activityMay be selenium dependent

Change in TSH with Age

Mariotto, et al. JCEM 1993: 77(5), 1130-1134

Change in T4 and T3

Mariotto, et al. JCEM 1993: 77(5), 1130-1134

Hypothyroidism

More common with advancing age 7-14 % of elderly have TSH above nl

range, more women than men Higher incidence in iodine replete areas Autoimmune is the most common cause,

followed by surgical

Elevated TSH with aging

Canaris et al, Archives of Int Med: 2000;160:526

Diagnosis

Symptoms can be the same as in younger patients, but more often ignored as they are attributed to “aging”

Fatigue and weakness were reported by more than 50%, but the following sxs were less commonly reported: cold intolerance, weight gain, paresthesias, and muscle

cramps Can score lower on MMSE along with other

memory and neurocognitive testing

Associated Findings

PE: Bradycardia, diastolic hypertension, pericardial effusion

Labs: Elevated TSH, low FT4 Other potential findings:

Hyponatremia elevated CKelevated LDL

Treatment

Levothyroxine replacement Start with lower dosage—0.25-0.5 mcg/kg instead of 1.6

mcg/kg as in young See if tolerate, and then can increase by 12.5-25 mcg q 4-

6 weeks One study showed that if no cardiac dz present, elderly

could tolerate full dose If have underlying cardiac disease, may not be able to

tolerate dose that would normalize TSH Final dose may be 40 mcg lower than in comparable young

Hyperthyroidism

Not as common as hypothyroidism Prevalence < 0.5% of elderly Subclinical hyperthyroidism is more

common: 1-5%, but most studies say < 2.5%

Presentation

Classically present with different symptoms

Weight loss, depression, and agitation dominate, leading to it being called “apathetic hyperthyroidism”

Sympathetic sxs less common like tremor or hyperactivity

Cardiovascular Findings

A-fib occurs in 15% of pts with hyperthyroidism, but is more common in elderly

CV complications are more common in elderly: ischemic heart dz, dysrhythmias, hypertensive hd

So think about getting TFTs in pts presenting with atrial fibrillation, worsening heart failure, systolic hypertension, or deteriorating ischemic heart disease

Effects on Bone

Leads to decreased BMD, especially in post-menopausal women

Treatment of hyperthyroidism improves BMD, but not back to baseline

One study showed a doubling of risk of death from fractured femur in treated pts

Need to get DXA and consider bisphosphonates in pts with hx of hyperthyroidism

Thyroid Nodules

Incidence of nodules increases with age Palpable nodules found in 5% of pts >60 Autopsy studies show 90% in women >70 U/S show 50% of women over 50 have nodules

Causes of goiter in older population Nontoxic MNG: 51% Toxic MNG: 23% Single nodule: 8% Graves: 5% Hashimotos: 4%

Thyroid Cancer

See same cancers as in young, but some differences

Ratio of Papillary:Follicular goes from 4:1 to 2:1

Female:male ratio narrows Decreased 10 yr survival with older age

Women <20 have 100%Women >60 have <5%

Thyroid Cancer

Increased recurrance rate in older pts PTC/Follicular risk of recurrance and death

<50: 10% and 3% >50: 32% and 30%

Direct extension worse in elderly 67% recurrance, 60% death in older 12% and 4% in young

Distant mets more deadly in older 96% vs 63%

Cady B, Sedgwick CE, Meissner WA, et al. Risk factor analysis in differentiated

thyroid cancer. Cancer 43:810-820, 1979

Anaplastic Thyroid Cancer

Peak incidence in 60’s, and more than 65% occur in pts older than 65

1-2% of all thyroid cancers Usually presents as a rapidly growing mass with local

sxs Often caused by transformation of pre-existing

differentiated thyroid cancer or longstanding goiter Older pts have worse prognosis 5 yr survival of 7%, mean survival of 11 months

Thyroid Lymphoma

Only .5-5% of all thyroid cancers Peak incidence form 50-80 Presents as rapidly enlarging goiter, usually

in someone with long standing Hashimoto’s Dx can be difficult since FNA will just show

lymphocytes. Can do flow cytometry Treatment is chemotherapy

Androgens

Testosterone levels in men decline continuously starting at age 30

There is no abrupt decrease similar to menopause

Testosterone is lower in men with chronic illness, obesity, metabolic syndrome, etc

SHBG goes up in elderly, lowering free T even more

Longitudinal Changes in Testosterone

Tes

tost

eron

eT

esto

ster

one

(nm

ol/L

) (

nmol

/L)

Age (Years)Age (Years)

1010

1212

1414

1616

1818

2020

3030 4040 5050 6060 7070 8080 9090

(177)(177)

(144)(144)(151)(151)

(158)(158)

(109)(109)

(43)(43)

Adapted from Harman SM, et al. Adapted from Harman SM, et al. J Clin Endocrinol MetabJ Clin Endocrinol Metab. 2001;86:724-731.. 2001;86:724-731.

Incidence

Not every man develops low T, unlike women who all go through menopause

Incidence varies in different studies50% of men >70 y/o vs.3% of healthy men

Health status may be a significant factor

Physiology

Testosterone production decreases with age All levels of the HPT axis are affected

LH/FSH are higher than in younger men, but not as high as expected for degree of low T, indicating loss of normal feedback

LH/FSH response to GnRH not as coordinated Less synchrony in LH pulses and T production Decreased ability of testes to make T

Effects of Low Testosterone

Decreased muscle mass and strength Decreased bone mineral density Decreased libido and sexual functioning

Low nitric oxide synthase is seen in hypogonadal men. NOS needed for PDE to work

Increased fat mass Anemia Dysthymia

Testosterone and Mortality

Several studies have shown decreased survival in men with lower T

Rancho Bernardo study showed that men in the lowest quartile of testosterone (<241 ng/dL) were 40% more likely to die over the next 20 years than those with higher levels

The increased risk of death in men with low testosterone levels was independent of multiple risk factors, including age, adiposity, and lifestyle

No studies have shown replacement increases survival. Unclear is cause:effect or association

Araujo AB, Kupelian V, Page ST, Handelsman DJ, Bremner WJ, McKinlay JB.Sex steroids and all-cause and cause-specific mortality in men. Arch Intern Med. 2007 Jun 25;167(12):1252-60

Effect of T on Survival

Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR.Low serum testosterone and mortality in male veterans. Arch Intern Med. 2006 Aug 14-28;166(15):1660-5

Definition and Diagnosis

Normal ranges of T based on young men Does this correlate to elderly? Draw total T before 0900

>350 ng/dl—no deficiency<230 mg/dl—deficient230-350 ng/dl: need to check free T

Benefits of Replacement

Benefit only shown in men who have low T Decreases fat mass and increases muscle

mass, but not dramatic Improved sexual functioning and libido Improves bone mineral density, but no fracture

data No good data on cognition Can improve quality of life

Should We Replace?

An expert panel of the Endocrine Society recommended against testosterone therapy for all older men with low testosterone levels.

Instead the panel suggested that “clinicians consider offering testosterone therapy on an individualized basis to older men with consistently low testosterone levels on more than one occasion and significant symptoms of androgen deficiency, after appropriate discussion of the uncertainties of the risks and benefits of testosterone therapy in older men”.

The panel’s recommendations were guided by the recognition of the paucity and low quality of evidence, and that high quality evidence of the efficacy and safety will not be available for a very long time.

Androgen deficiency in Women

As in men, testosterone levels decline with aging, particularly after oophorectomy or adrenal failure

By age 40, T levels are 50% of age 20 However, levels don’t fall at menopause like estrogen

does Hard to biochemically define because free T assays

are not good at the lower range and total not as reliable due to more SHBG variation

Testosterone levels not associated with sexual functioning in some studies

Benefits of Replacement?

Controversial that disorder even exists Decreased sexual desire is reported in 25-

53% of women, but not always perceived as a problem

Maybe improvement in BMD Conflicting results on body mass

Androgen Replacement

Multiple studies looked at transdermal testosterone replacement in surgically and naturally menopausal women on estrogen

Patch of 300 mcg worn for 24 weeks increased satisfying sexual encounters by 1-2 episodes per month—statistically significant

Other measures of mood, sense of well being, libido, and distress had mixed outcomes

No long term safety data

Outcomes

Treatment effect was not dependent on baseline testosterone levels

No significant difference in surgical or natural menopausal women except for number of satisfying encounters

Women in the 300 mcg group had testosterone levels at or above the upper range of normal

Summary

300 mcg testosterone patch modestly improved sexual functioning, but this is clinically meaningful

Baseline testosterone had no bearing on outcome, so not useful for diagnosing “androgen deficiency”

Growth Hormone

Similar properties to sex steroids Improve lean body mass and muscle

strength Decrease fat mass Improve BMD Improve sense of well being

Growth Hormone Deficiency

Increased fat and decreased lean mass Sarcopenia Increased lipids Increased CV disease, impaired cardiac

function Decreased BMD

GH Changes with Aging

GH Declines as we age Sex steroids have a significant impact on

GH levelsThe higher the testosterone, the higher the GH

levels Obesity also is a factor

The more overweight a person is, the lower their GH levels

Relationship of Age, Weight and Testosterone to GH

Iranmanesh, A, et al, Eur J Endo 1998;139:59-71

GH and Aging

Since muscle and strength decline with age, would supplementing GH be beneficial?

GH supplementation in pts who are deficient has been shown to: improve QOL Increase lean body mass Decrease fat mass--especially central Increase BMD

Risks of Supplementation

Possible increased risk of malignancy Increased insulin resistance Increased edema, arthralgias, and carpal

tunnel syndrome Some studies showed critically ill pts (ICU,

CHF) had higher mortality when treated with GH

Answer?

Don’t know if decline in GH with aging is adaptive or maladaptive

GH secretogogues may be an answer in the future

Currently, can’t recommend GH replacement for average aging patient

Osteoporosis

Peak bone mass is attained by age 20 Thereafter, bone is lost at a steady rate In women, there is an increase in BMD

loss for the 5-10 years after menopause

Rate of bone Loss

Dashed=trabecular

Solid=cortical

Khosla, et al. Pathophysiology of Age Related Bone Loss and Osteoporosis. Endo Metab Clin N Amer, DEC 2005: 1015-1030

Fracture Incidence

Khosla, et al. Pathophysiology of Age Related Bone Loss and Osteoporosis. Endo Metab Clin N Amer, DEC 2005: 1015-1030

Post-menopausal Osteoporosis

After menopause, estradiol levels fall to 10-15% of previous levels

Bone resorption increases by 90%, while formation increases by 45%

Estrogen inhibits osteoclast function and multiple cytokines that increase bone resorption. Without estrogen, these processes increase

Post-menopausal Osteoporosis

Other contributing factors: Vit D deficiency Secondary hyperparathyroidism Decreased calcium intake and increased calcium

secretion Never attaining good peak BMD Decreased GH levels Secondary causes

Also have impaired bone formation due to GH defic, estrogen defic,

Osteoporosis in Men

Men lose half as much bone as women and have 1/3 the number of fractures

Main cause is decreased testosterone, but estrogen has the main effect on bone

Therefore do not want to give aromatase inhibitors to men on androgen therapy—will decrease bone benefit

Estrogen Effect on BMD in Men

Khosla, et al. Pathophysiology of Age Related Bone Loss and Osteoporosis. Endo Metab Clin N Amer, DEC 2005: 1015-1030

Screening

The NOF recommends offering BMD testing to the following women:

1. All postmenopausal women under age 65 who have one or more additional risk factors for osteoporosis (besides menopause).

2. All women aged 65 and older regardless of additional risk factors. 3. Postmenopausal women who present with fractures (to confirm

diagnosis and determine disease severity). 4. Women who are considering therapy for osteoporosis, if BMD

testing would facilitate the decision. 5. Women who have been on hormone replacement therapy for

prolonged periods.

Screening in Men

NOF does not give specific guidelines ACP recommends:

clinicians periodically perform individualized assessment of risk factors for osteoporosis in

older men clinicians obtain DXA for men who are at increased risk for

osteoporosis and are candidates for drug therapy Main risk factors: age >70, low BMI, weight loss,

previous fracture, steroid use, inactivity, hypogonadism

Cortisol Axis

Age does not have a significant effect on CRH, ACTH, or cortisol levels

However, diurnal pattern seems to be altered, with higher levels later in the day

CRH evokes a greater ACTH and cortisol response in older pts

Stress response ACTH and cortisol release are actually 2-fold greater—seems to be a decreased sensitivity to negative feedback by cortisol

This is more prominent in women

DHEA

DHEA is not active, but it is converted to other androgens that are active

By age 80, DHEA levels are <10 % of young adult levels

ACTH which stimulates release of DHEA remain stable over this time

Likely due to decreased adrenal enzyme activity, like 3ß-HSD

DHEA Over Time

DHEA and Mortality

Multiple studies have shown that older men with lower levels of DHEA have increased mortality and lower functional status

There was no correlation seen in women DHEA replacement in adrenally insufficient pts has shown

improvement in a number of areas However, replacement in healthy elderly showed no

benefit in multiple studies It has improved sense of well being in pts with

depression, schizophrenia, and some immune mediated dzs like SLEc

Diabetes

Prevalence of DM increases with aging Changes that occur with aging

Decreased insulin secretion Decreased insulin action/increased resistance Alteration of hepatic glucose output Increased obesity Change in diet

These changes associated with genetic background increase DM in the elderly

Prevalence of DM

Third NHANES Survey 1988-1994

Presentation

May not be classic Glycemic threshold in kidney higher so

may not have polyuria Have impaired thirst drive so may not have

polydypsia Complaints may be more non-specific Often will present with a complication like

CVA, HONK, or MI

Hypoglycemia

The risk of severe hypoglycemia with oral agents or insulin increases exponentially in the elderly

Due to: Impaired secretion of counter-regulatory hormones

like glucagon Reduced awareness of autonomic symptoms Decreased ability to function with a low sugar which

decreases their ability to treat themselves Primary treatment is prevention!

Goals of Treatment

Need to be individualized Don’t need to be as aggressive in pts with

shorter life expectancy or significant co-morbidities

For some, goal is to prevent hyperglycemic sxs:Fasting sugar <180Post-prandial <250

Medications

If mild hyperglycemia, consider meds that will not cause hypoglycemia:Metformin (as long as GFR>60)α-glucosidase inhibitorsDPP4 inhibitors

Caution with TZDs Caution with sulfonylureas and meglitinides

Glyburide

Elimination is decreased with age Leads to more glucose lowering effect in elderly

than in young Cleared renally Metabolites are active All this leads to increased risk of severe

hypoglycemia Other sulfonlyureas do not have these properties

Questions?