Transcript Endo_and_Aging

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
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Thyroid Axis
Changes with Aging
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Decreased pituitary responsiveness
 Less
TSH response to TRH
 Less rise in TSH to low T4/T3
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Thyroid does not respond to TSH as well
 Less
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T4 response to TSH surge
Decreased peripheral conversion of T4 to
T3 due to decreased 5’ deiodinase activity
 May
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
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Elevated TSH with aging
Canaris et al, Archives of Int Med: 2000;160:526
Diagnosis
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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
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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:
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 Hyponatremia
 elevated
CK
 elevated LDL
Treatment
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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%
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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
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Cardiovascular Findings
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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
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Leads to decreased BMD, especially in postmenopausal 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
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Incidence of nodules increases with age
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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
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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
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 Women
<20 have 100%
 Women >60 have <5%
Thyroid Cancer
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Increased recurrance rate in older pts
 PTC/Follicular
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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
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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
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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
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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
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Longitudinal Changes in Testosterone
Testosterone
(nmol/L)
20
18
(177)
(144)
(151)
16
(109)
14
(43)
(158)
12
10
30
40
50
60
Age (Years)
Adapted from Harman SM, et al. J Clin Endocrinol Metab. 2001;86:724-731.
70
80
90
Incidence
Not every man develops low T, unlike
women who all go through menopause
 Incidence varies in different studies
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 50%
of men >70 y/o vs.
 3% of healthy men
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Health status may be a significant factor
Physiology
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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
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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
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Increased fat mass
Anemia
Dysthymia
Testosterone and Mortality
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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
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 >350
ng/dl—no deficiency
 <230 mg/dl—deficient
 230-350 ng/dl: need to check free T
Benefits of Replacement
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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?
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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
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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 2553% of women, but not always perceived
as a problem
 Maybe improvement in BMD
 Conflicting results on body mass
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Androgen Replacement
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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
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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”
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Growth Hormone
Similar properties to sex steroids
 Improve lean body mass and muscle
strength
 Decrease fat mass
 Improve BMD
 Improve sense of well being
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Growth Hormone Deficiency
Increased fat and decreased lean mass
 Sarcopenia
 Increased lipids
 Increased CV disease, impaired cardiac
function
 Decreased BMD
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GH Changes with Aging
GH Declines as we age
 Sex steroids have a significant impact on
GH levels
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 The
higher the testosterone, the higher the
GH levels
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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
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Since muscle and strength decline with age,
would supplementing GH be beneficial?
GH supplementation in pts who are deficient has
been shown to:
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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
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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
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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
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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
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Post-menopausal Osteoporosis
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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
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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
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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
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The NOF recommends offering BMD testing to the
following women:
All postmenopausal women under age 65 who have one
or more additional risk factors for osteoporosis (besides
menopause).
All women aged 65 and older regardless of additional
risk factors.
Postmenopausal women who present with fractures (to
confirm diagnosis and determine disease severity).
Women who are considering therapy for osteoporosis, if
BMD testing would facilitate the decision.
Women who have been on hormone replacement
therapy for prolonged periods.
Screening in Men
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NOF does not give specific guidelines
ACP recommends:
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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
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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
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DHEA Over Time
DHEA and Mortality
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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
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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
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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
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Hypoglycemia
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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
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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 comorbidities
 For some, goal is to prevent
hyperglycemic sxs:
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 Fasting
sugar <180
 Post-prandial <250
Medications
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If mild hyperglycemia, consider meds that
will not cause hypoglycemia:
 Metformin
(as long as GFR>60)
 α-glucosidase inhibitors
 DPP4 inhibitors
Caution with TZDs
 Caution with sulfonylureas and
meglitinides
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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
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Questions?